Medical Devices; Classification/Reclassification of Immunohistochemistry Reagents and Kits

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 864

[Docket No. 94P-0341]

RIN 0910-ZA10

Medical Devices; Classification/Reclassification of

Immunohistochemistry Reagents and Kits

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule

to classify/reclassify immunohistochemistry reagents and kits (IHC's)

into three classes depending on intended use. FDA is classifying/

reclassifying into class I (general controls) and exempt from premarket

notification requirements IHC's used as adjunctive tests and presenting

a low risk to public health. FDA is classifying/reclassifying into

class II (special control) IHC's that detect or measure certain target

analytes and that provide prognostic or predictive data that is not

confirmed by routine histopathologic control specimens. The results of

the class II IHC's are reported independently to the clinician, and the

performance claims are widely accepted and supported by valid

scientific evidence. FDA is classifying/reclassifying into class III

(premarket approval) IHC's intended for any other use. The scope of

products covered by this final rule includes both pre-1976 devices that

have not been previously classified, as well as post-1976 devices that

are statutorily classified into class III. The intent of this final

rule is to regulate pre-1976 devices and post-1976 devices in a

consistent fashion. Therefore, FDA is classifying or reclassifying

these products as applicable.

EFFECTIVE DATE: This rule is effective August 17, 1998.

FOR FURTHER INFORMATION CONTACT: Max Robinowitz, Center for Devices and

Radiological Health (HFZ-440), Food and Drug Administration, 2098

Gaither Rd., Rockville, MD 20850, 301-594-1293, ext. 136, or FAX 301-

594-5941.

SUPPLEMENTARY INFORMATION:

I. Background

Immunohistochemistry (IHC) is the diagnostic laboratory practice

that combines immunologic techniques, using specially prepared antibody

reagents, with the examination of intact cells and tissues under the

microscope by a pathologist or other trained laboratory scientist. An

IHC device is an in vitro diagnostic reagent or test kit that uses

immunological methods to identify antigens in tissues or intact cells.

An IHC reagent is the primary antibody of an IHC assay that is

developed to specifically target, react to, or combine with, a

particular cellular or tissue constituent, or antigen, using specific

immunological characteristics of the antibody. IHC's may be used

together with a secondary or reporter antibody, buffers, washing

solutions, and controls. If an IHC primary antibody reagent is sold

separately, there should be recommendations for what ancillary reagents

and equipment should be used with the IHC reagent to achieve the

performance characteristics claimed for the primary IHC reagent. If the

IHC is marketed as a test kit, there should be performance data with

the finished test kit.

II. Highlights of the Final Rule

In response to public comments, FDA has revised and clarified

certain provisions of the final regulation. The revisions maintain the

protection of the public health while reducing the regulatory burden on

manufacturers by lowering the classification of a number of IHC's. The

most significant changes from the proposed rule are as follows:

1. Under the final rule, most IHC's are being classified as class I

devices, exempt from premarket notification. Class I includes all IHC's

being used as adjuncts to conventional histopathologic diagnostic

examination.

2. The definition of class II IHC's has been changed to include

IHC's that are not directly confirmed by routine histopathologic

control specimens and with claims that are widely accepted and

supported by valid scientific evidence. Class II IHC's now include such

products as estrogen and progesterone receptors (ER/PR's).

3. The definition of class III IHC's has been narrowed to include

only those IHC's that do not meet the criteria for class I or II.

4. Accordingly, the rule lessens the regulatory burden for bringing

IHC's to market because most IHC's are now classified/reclassified as

class I or II. As post-1976 devices, most IHC's previously were class

III devices under section 513(f)(1) of the Federal Food, Drug, and

Cosmetic Act) (the act) (21 U.S.C. 360c(f)(1)).

In addition, the agency clarifies and reinforces the following

points:

1. This final rule regulates only IHC's being used for diagnostic

purposes. Neither the proposed rule nor the final rule would require

submissions for reagents or test kits used for research purposes only.

Nor does FDA require manufacturers of such research use only reagents

or test kits to comply with general controls; and

2. IHC's used for diagnostic purposes have been and will continue

to be subject to the current good manufacturing practices (CGMP's)

under the act. The requirement to comply with CGMP's is a general

control that all devices must meet (unless expressly exempt under

section 513(d)(2)(A)) of the act without regard to their level of

classification or whether they have been previously classified. (See H.

Rept. 94-853 at 17 (1976).)

III. The Final Rule

A. General Approach

FDA believes that the final rule establishes reasonable

requirements that can be implemented by the regulated industry without

unnecessary burden. To ensure safety and effectiveness, all classes of

IHC's will be subject to the following general controls: (1) Labeling

requirements for in vitro devices (Sec. 809.10 (21 CFR 809.10)), (2)

compliance with CGMP's, (3) registration and listing, (4) recordkeeping

and medical device reporting (MDR), and (5) labeling for prescription

use (Sec. 801.109 (21 CFR 801.109)). FDA has determined that these

controls are necessary for a reasonable assurance of safety and

effectiveness.

B. Class I Exempt From Premarket Notification

In the final rule, FDA has broadened the class I identification to

include all adjunctive IHC's. This change places the majority of IHC's

into class I. The final rule also modifies the language in the

regulation to clarify that class I IHC's are used to classify tumors.

In response to comments submitted on the proposed rule, FDA

reconsidered the regulation of class I IHC's and decided to exempt them

from premarket notification (510(k)) requirements. In considering

whether to exempt class I devices from premarket notification, FDA

focuses on whether notification for the type of device is necessary for

the protection of the public health. For the devices exempted from

premarket notification by this rule, FDA has concluded that

notification is unnecessary primarily for the following reasons:

1. The devices do not have a significant history of false or

misleading performance claims or of risks

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associated with inherent characteristics of the device, such as device

design or materials. When making such determinations, FDA generally has

considered the frequency, persistence, cause, or seriousness of such

performance claims or risks, as well as other relevant factors.

FDA is unaware of IHC failure being reported in the MDR data base.

IHC failures have been reported in the medical literature; the risks of

such failure, however, are mitigated by widely accepted practices that

are based on valid scientific evidence.

2. In general, FDA will exempt a device from premarket notification

when the following factors apply: (a) Characteristics of the device

necessary for its safe and effective performance are well established;

(b) anticipated changes in the device that could affect safety and

effectiveness will either be readily detectable by users by visual

examination or other means, such as routine testing, before causing

harm (e.g. testing of a clinical laboratory reagent with positive and

negative controls), or not materially increase the risk of injury,

incorrect diagnosis, or ineffective treatment; and (c) any changes in

the device would not be likely to result in a change in the device's

classification. FDA makes these determinations based on its knowledge

of the device, including past experience and relevant reports or

studies on device performance.

The characteristics of IHC's are well established. Although the

method is not generally quantitative, the results generated using this

technology are sufficiently accurate and precise to support

subclassification of tumors (neoplasms), and detection and measurement

of the presence or absence of clinically significant target analytes.

There are sufficient quality assurance techniques in the use of IHC's

to enhance the precision of the methodology and minimize the risks of

misdiagnosis.

Because class I IHC's are identified as those that are used

adjunctively to support conventional histopathological diagnosis and

are controlled by readily available internal and external control

materials, minor changes to the IHC would not materially increase the

risk of injury, incorrect diagnosis, or ineffective treatment.

Adjunctive test results are evaluated and incorporated into the

diagnostic interpretation by the pathologist and are not usually

reported directly to the clinician. Because laboratories certified

under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) are

required to run positive and negative quality control samples with all

special stains, reagent failures are likely to be easily identified by

pathologists. In addition, most slides will have normal along with

abnormal tissue included as part of the tissue sample on the slide and

this juxtaposition affords an additional opportunity to identify

inappropriate or uncommon staining patterns.

Manufacturers are reminded that exemption from the requirement of

premarket notification is not an exemption from CGMP's and the other

applicable general controls.

Because IHC's have been classified in accordance with the risk

associated with their intended use, a change in intended use or

indications for use of an IHC would likely result in a

reclassification. Such a change would not be considered minor and would

probably require a submission to the agency. For a discussion of

whether a change to a device would require a manufacturer to submit a

510(k), see the FDA's guidance entitled ``Deciding when to Submit a

510(k) for a Change to an Existing Device.''

C. Class II

In contrast to all adjunctive IHC's being placed into class I, the

final rule clarifies that class II IHC's are IHC's that generate

results that are not directly confirmed by routine histopathologic

internal and external control specimens. Class II IHC's are intended to

provide information that is ordinarily reported as independent

diagnostic information to the clinician. For an IHC to be classified

into class II, the claims associated with this information must be

widely accepted and supported by valid scientific evidence. FDA

believes that the manufacturer/sponsor can establish the acceptance of

the intended use of the IHC and valid scientific evidence through

sponsor-supported studies or scientific literature references,

materials from professional educational seminars, and/or the citation

of practice standards or guidelines, as described in the special

control noted in the paragraph below. These IHC's must be developed and

established by validation and correlation testing with well

characterized clinical specimens that support the intended use of the

IHC test system as an independent prognostic or predictive marker. FDA

believes that providing valid scientific evidence of performance claims

that are widely accepted and complying with the general controls should

be sufficient to ensure the safe and effective use of these IHC's.

Class II IHC's are subject to a special control entitled ``FDA

Guidance for Submission of Immunohistochemistry Applications to the

FDA,'' FDA, Center for Devices and Radiologic Health, 1998. The updated

guidance will assist sponsors in collecting and presenting data to FDA

to establish that the claims associated with use of the device are

widely accepted and that there is valid scientific evidence to support

performance claims with clinical specimens. The special control is also

intended to provide guidance to manufacturers about labeling for use of

the device. This guidance has been issued as a Level 2 guidance

consistent with the ``Good Guidance Practices'' (GGP's) FDA adopted for

the development, issuance, and use of guidance documents (62 FR 8961,

February 27, 1997). Persons interested in obtaining this document

should refer to section VI of this document entitled ``Access to the

Special Control.''

Several comments urged that IHC's for ER/PR's be classified as

class II devices rather than as class III, as proposed. FDA concurs

with this suggestion. By using well characterized clinical specimens

and validating their IHC's against appropriate FDA approved chemical

receptor assays, manufacturers can reliably characterize these products

and support their clearance as class II devices. FDA believes that

class II classification can now safely apply to IHC's for ER/PR's,

including hormone receptors in breast cancer, because clinical reliance

on such testing has been established in the medical literature and the

information derived from such test results are well understood.

D. Class III

In response to comments on the proposed rule and changes to the

class II classification, FDA has narrowed the scope of the class III

identification. Under the final rule, IHC's that do not meet the

criteria for class I or II will be classified into class III.

Manufacturers of these IHC's must submit valid scientific evidence to

support the new intended uses. An example of a class III IHC would be

markers used to identify new, clinically significant target analytes in

tissue specimens that cannot be confirmed by conventional

histopathologic examination.

FDA has amended proposed Sec. 864.1860(c) to indicate that

postamendment class III IHC's cannot be commercially distributed unless

the manufacturer has an approval under section 515 of the act (21

U.S.C. 360e).

IV. The Proposed Rule

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

published a

[[Page 30134]]

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