30132 Federal Register / Vol. 63, No. 106 /Wednesday, June 3, 1998 /Rules and Regulations

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.

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

(§ 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 (§ 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
Federal Register / Vol. 63, No. 106 /Wednesday, June 3, 1998 /Rules and Regulations 30133

associated with inherent characteristics

of the device, such as device design or

materials. When making such

determinations, FDA generally has

considered the frequency, persistence,

cause, or seriousness of such

performance claims or risks, as well as

other relevant factors.

FDA is unaware of IHC failure being

reported in the MDR data base. IHC

failures have been reported in the

medical literature; the risks of such

failure, however, are mitigated by

widely accepted practices that are based

on valid scientific evidence.

2. In general, FDA will exempt a

device from premarket notification

when the following factors apply: (a)

Characteristics of the device necessary

for its safe and effective performance are

well established; (b) anticipated changes

in the device that could affect safety and

effectiveness will either be readily

detectable by users by visual

examination or other means, such as

routine testing, before causing harm (e.g.

testing of a clinical laboratory reagent

with positive and negative controls), or

not materially increase the risk of

injury, incorrect diagnosis, or ineffective

treatment; and (c) any changes in the

device would not be likely to result in

a change in the device’s classification.

FDA makes these determinations based

on its knowledge of the device,

including past experience and relevant

reports or studies on device

performance.

The characteristics of IHC’s are well

established. Although the method is not

generally quantitative, the results

generated using this technology are

sufficiently accurate and precise to

support subclassification of tumors

(neoplasms), and detection and

measurement of the presence or absence

of clinically significant target analytes.

There are sufficient quality assurance

techniques in the use of IHC’s to

enhance the precision of the

methodology and minimize the risks of

misdiagnosis.

Because class I IHC’s are identified as

those that are used adjunctively to

support conventional histopathological

diagnosis and are controlled by readily

available internal and external control

materials, minor changes to the IHC

would not materially increase the risk of

injury, incorrect diagnosis, or ineffective

treatment. Adjunctive test results are

evaluated and incorporated into the

diagnostic interpretation by the

pathologist and are not usually reported

directly to the clinician. Because

laboratories certified under the Clinical

Laboratory Improvement Amendments

of 1988 (CLIA) are required to run

positive and negative quality control

samples with all special stains, reagent

failures are likely to be easily identified

by pathologists. In addition, most slides

will have normal along with abnormal

tissue included as part of the tissue

sample on the slide and this

juxtaposition affords an additional

opportunity to identify inappropriate or

uncommon staining patterns.

Manufacturers are reminded that

exemption from the requirement of

premarket notification is not an

exemption from CGMP’s and the other

applicable general controls.

Because IHC’s have been classified in

accordance with the risk associated with

their intended use, a change in intended

use or indications for use of an IHC

would likely result in a reclassification.

Such a change would not be considered

minor and would probably require a

submission to the agency. For a

discussion of whether a change to a

device would require a manufacturer to

submit a 510(k), see the FDA’s guidance

entitled ‘‘Deciding when to Submit a

510(k) for a Change to an Existing

Device.’’

C. Class II

In contrast to all adjunctive IHC’s

being placed into class I, the final rule

clarifies that class II IHC’s are IHC’s that

generate results that are not directly

confirmed by routine histopathologic

internal and external control specimens.

Class II IHC’s are intended to provide

information that is ordinarily reported

as independent diagnostic information

to the clinician. For an IHC to be

classified into class II, the claims

associated with this information must

be widely accepted and supported by

valid scientific evidence. FDA believes

that the manufacturer/sponsor can

establish the acceptance of the intended

use of the IHC and valid scientific

evidence through sponsor-supported

studies or scientific literature

references, materials from professional

educational seminars, and/or the

citation of practice standards or

guidelines, as described in the special

control noted in the paragraph below.

These IHC’s must be developed and

established by validation and

correlation testing with well

characterized clinical specimens that

support the intended use of the IHC test

system as an independent prognostic or

predictive marker. FDA believes that

providing valid scientific evidence of

performance claims that are widely

accepted and complying with the

general controls should be sufficient to

ensure the safe and effective use of these

IHC’s.

Class II IHC’s are subject to a special

control entitled ‘‘FDA Guidance for

Submission of Immunohistochemistry

Applications to the FDA,’’ FDA, Center

for Devices and Radiologic Health, 1998.

The updated guidance will assist

sponsors in collecting and presenting

data to FDA to establish that the claims

associated with use of the device are

widely accepted and that there is valid

scientific evidence to support

performance claims with clinical

specimens. The special control is also

intended to provide guidance to

manufacturers about labeling for use of

the device. This guidance has been

issued as a Level 2 guidance consistent

with the ‘‘Good Guidance Practices’’

(GGP’s) FDA adopted for the

development, issuance, and use of

guidance documents (62 FR 8961,

February 27, 1997). Persons interested

in obtaining this document should refer

to section VI of this document entitled

‘‘Access to the Special Control.’’

Several comments urged that IHC’s for

ER/PR’s be classified as class II devices

rather than as class III, as proposed.

FDA concurs with this suggestion. By

using well characterized clinical

specimens and validating their IHC’s

against appropriate FDA approved

chemical receptor assays, manufacturers

can reliably characterize these products

and support their clearance as class II

devices. FDA believes that class II

classification can now safely apply to

IHC’s for ER/PR’s, including hormone

receptors in breast cancer, because

clinical reliance on such testing has

been established in the medical

literature and the information derived

from such test results are well

understood.

D. Class III

In response to comments on the

proposed rule and changes to the class

II classification, FDA has narrowed the

scope of the class III identification.

Under the final rule, IHC’s that do not

meet the criteria for class I or II will be

classified into class III. Manufacturers of

these IHC’s must submit valid scientific

evidence to support the new intended

uses. An example of a class III IHC

would be markers used to identify new,

clinically significant target analytes in

tissue specimens that cannot be

confirmed by conventional

histopathologic examination.

FDA has amended proposed

§ 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
30134 Federal Register / Vol. 63, No. 106 /Wednesday, June 3, 1998 /Rules and Regulations

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 § 864.4010 (21

CFR 864.4010), and subject to

§ 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

§ 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 § 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

§ 807.85(b)(1) (21 CFR 807.85(b)(1)),

which exempts ‘‘grandfathered’’

products from 510(k) review.

These comments misunderstand the

meaning of § 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 § 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
Federal Register / Vol. 63, No. 106 /Wednesday, June 3, 1998 /Rules and Regulations 30135

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 (§ 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

§ 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-tolaboratory 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

§ 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
30136 Federal Register / Vol. 63, No. 106 /Wednesday, June 3, 1998 /Rules and Regulations

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 standalone test to determine prognosis

independent of other findings; (b) the

user must use clinically wellcharacterized 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 sitespecific 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 ‘‘technologyspecific’’ and limited to only those

devices that employ monoclonal or

polyclonal antibodies. The comment
Federal Register / Vol. 63, No. 106 /Wednesday, June 3, 1998 /Rules and Regulations 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
30138 Federal Register / Vol. 63, No. 106 /Wednesday, June 3, 1998 /Rules and Regulations

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 § 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 § 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
Federal Register / Vol. 63, No. 106 /Wednesday, June 3, 1998 /Rules and Regulations 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(§ 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 reexamine 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
30140 Federal Register / Vol. 63, No. 106 /Wednesday, June 3, 1998 /Rules and Regulations

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-OnDemand 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
Federal Register / Vol. 63, No. 106 /Wednesday, June 3, 1998 /Rules and Regulations 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 Paraffinembedded 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:
30142 Federal Register / Vol. 63, No. 106 /Wednesday, June 3, 1998 /Rules and Regulations

§ 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 § 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

DEPARTMENT OF TRANSPORTATION

Coast Guard

33 CFR Part 100

[CGD 05–98–035]

RIN 2115–AE46

Special Local Regulations for Marine

Events; The Great Chesapeake Bay

Swim Event, Chesapeake Bay, MD

AGENCY: Coast Guard, DOT.

ACTION: Notice of implementation.

SUMMARY: This notice implements 33

CFR 100.507 for the Great Chesapeake

Bay Swim Event to be held on June 14,

1998. These special local regulations are

needed to provide for the safety of

participants and spectators on the

navigable waters during this event. The

effect will be to restrict general

navigation in the regulated area for the

safety of participants in the swim and

their attending personnel.

EFFECTIVE DATE: 33 CFR 100.507 is

effective from 10 a.m. until 4 p.m., on

June 14, 1998.

FOR FURTHER INFORMATION CONTACT:

LT J. Driscoll, Marine Events

Coordinator, Commander, Coast Guard

Activities Baltimore, 2401 Hawkins

Point Rd., Baltimore, MD 21226–1797,

(410) 576–2676.

SUPPLEMENTARY INFORMATION: The

March of Dimes will sponsor the Great

Chesapeake Bay Swim Event on

Chesapeake Bay in the vicinity of the

William P. Lane Jr. Memorial Twin

Bridges. Approximately 600 swimmers

will start from Sandy Point State Park

and swim between the William P. Lane

Jr. Memorial Twin Bridges to the

Eastern Shore. A large fleet of support

vessels will be accompanying the

swimmers. Therefore, to ensure the

safety of the participants and support

vessels, 33 CFR 100.507 will be in effect

for the duration of the event. Under

provisions of 33 CFR 100.507, no

vessels may enter the regulated area

without permission of the Coast Guard

patrol commander. Vessel traffic will be

permitted to transit the regulated area as

the swim progresses. As a result,

maritime traffic should not be

significantly disrupted.

Dated: May 20, 1998.

Roger T. Rufe, Jr.

Vice Admiral, U.S. Coast Guard Commander,

Fifth Coast Guard District.

[FR Doc. 98–14705 Filed 6–2–98; 8:45 am]

BILLING CODE 4910–15–M

DEPARTMENT OF TRANSPORTATION

Coast Guard

33 CFR Part 100

[CGD01–98–057]

RIN 2115–AE46

Special Local Regulation: Fireworks

Displays Within the First Coast Guard

District

AGENCY: Coast Guard, DOT.

ACTION: Notice of Implementation.

SUMMARY: This document provides

notice of the dates and times of the

special local regulations contained in 33

CFR 100.114, Fireworks Displays

Within the First Coast Guard District.

All vessels will be restricted from

entering the area of navigable water

within a 500-yard radius of the

fireworks launch platform for each

event listed in the table below.

Implementation of these regulations is

necessary to control vessel traffic within

the regulated area to ensure the safety of

spectators.

EFFECTIVE DATE: The regulations in 33

CFR 100.114 are effective from one hour

before the scheduled start of the event

until thirty minutes after the last

firework is exploded for each event

listed in the table below. The events are

listed chronologically by month with

their corresponding number listed in the

special local regulations, 33 CFR

100.114.

ADDRESSES: Comments should be

mailed to Commander (osr), First Coast

Guard District, Captain John Foster

Williams Federal Building, 408 Atlantic

Ave., Boston, MA 02110–3350, or may

be hand delivered to Room 734 at the

same address, between 8 a.m. and 4

p.m., Monday through Friday, except

federal holidays. Comments will

become part of this docket and will be

available for inspection or copying at

the above address.

FOR FURTHER INFORMATION CONTACT:

Lieutenant Commander Mark A.

Cawthorn, Office of Search and Rescue

Branch, First Coast Guard District at

(617) 223–8460.

SUPPLEMENTARY INFORMATION: This

notice implements the special local