Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations 62243

(iii) Limitations. Administer as a

single intramuscular injection. Do not

slaughter swine within 24 days of

treatment. Consult your veterinarian for

assistance in the diagnosis, treatment,

and control of parasitism.

PART 556—TOLERANCES FOR

RESIDUES OF NEW ANIMAL DRUGS

IN FOOD

3. The authority citation for 21 CFR

part 556 continues to read as follows:

Authority: 21 U.S.C. 342, 360b, 371.

4. Section 556.225 is revised to read

as follows:

§ 556.225 Doramectin.

A tolerance of 0.1 part per million

(ppm) is established for parent

doramectin (marker residue) in liver

(target tissue) of cattle and 0.16 ppm in

liver of swine.

Dated: October 22, 1997.

Stephen F. Sundlof,

Director, Center for Veterinary Medicine.

[FR Doc. 97–30562 Filed 11–20–97; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 558

New Animal Drugs for Use in Animal

Feeds; Clopidol and Bacitracin Zinc

With Roxarsone

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is amending the

animal drug regulations to reflect

approval of an abbreviated new animal

drug application (ANADA) filed by

Alpharma Inc. The abbreviated NADA

provides for using approved clopidol,

bacitracin zinc, and roxarsone Type A

medicated articles to make Type C

medicated broiler chicken feeds used for

prevention of coccidiosis, improved

feed efficiency, improved pigmentation,

and increased rate of weight gain.

EFFECTIVE DATE: November 21, 1997.

FOR FURTHER INFORMATION CONTACT:

Jeffrey M. Gilbert, Center for Veterinary

Medicine (HFV–128), Food and Drug

Administration, 7500 Standish Pl.,

Rockville, MD 20855, 301–594–1602.

SUPPLEMENTARY INFORMATION: Alpharma

Inc., One Executive Dr., P.O. Box 1399,

Fort Lee, NJ 07024, is sponsor of

ANADA 200–207 that provides for

combining approved clopidol,

bacitracin zinc, and roxarsone Type A

medicated articles to make Type C

medicated feeds for broilers containing

clopidol 113.5 grams per ton (g/t) and

bacitracin zinc 4 to 25 g/t with

roxarsone 45.4 g/t. The Type C

medicated feed is used as an aid in the

prevention of coccidiosis caused by

Eimeria tenella, E. necatrix, E.

acervulina, E. brunetti, E. mivati, and E.

maxima, and for increased rate of

weight gain, improved feed efficiency,

and improved pigmentation.

Alpharma Inc.’s ANADA 200–207 is

approved as a generic copy of RhonePoulenc, Inc.’s NADA 44–016. The

ANADA is approved as of November 21,

1997 and 21 CFR 558.175 is amended to

reflect the approval. The basis for

approval is discussed in the freedom of

information summary.

In accordance with the freedom of

information provisions of 21 CFR part

20 and 514.11(e)(2)(ii), a summary of

safety and effectiveness data and

information submitted to support

approval of this application may be seen

in the Dockets Management Branch

(HFA–305), Food and Drug

Administration, 12420 Parklawn Dr.,

rm. 1–23, Rockville, MD 20857, from 9

a.m. and 4 p.m., Monday through

Friday.

The agency has determined under 21

CFR 25.33(a)(1) 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 558

Animal drugs, Animal feeds.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to the Commissioner

of Food and Drugs and redelegated to

the Center for Veterinary Medicine, 21

CFR part 558 is amended as follows:

PART 558—NEW ANIMAL DRUGS FOR

USE IN ANIMAL FEEDS

1. The authority citation for 21 CFR

part 558 continues to read as follows:

Authority: 21 U.S.C. 360b, 371.

§ 558.175 [Amended]

2. Section 558.175 Clopidol is

amended in paragraph (d)(1)(iii)(b) by

removing ‘‘No. 000061’’ and adding in

its place ‘‘Nos. 000061 and 046573.’’

Dated: November 7, 1997.

Stephen F. Sundlof,

Director, Center for Veterinary Medicine.

[FR Doc. 97–30564 Filed 11–20–97; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 809 and 864

[Docket No. 96N–0082]

RIN 0910–ZA03

Medical Devices; Classification/

Reclassification; Restricted Devices;

Analyte Specific Reagents

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is issuing a final

rule to classify/reclassify analyte

specific reagents (ASR’s) presenting a

low risk to public health into class I

(general controls), and to exempt these

class I devices from the premarket

notification (510(k)) requirements. FDA

is classifying/reclassifying ASR’s used

in certain blood banking tests as class II

(special controls) because general

controls are insufficient to provide a

reasonable assurance of safety and

effectiveness. Finally, ASR’s presenting

a high risk are being classified or

retained in class III (premarket

approval). FDA is also designating all

ASR’s as restricted devices under the

Federal Food, Drug, and Cosmetic Act

(the act), and establishing restrictions on

their sale, distribution and use. The

scope of products covered by this final

rule includes both pre-1976 devices,

which have not been previously

classified, as well as post-1976 devices,

which are statutorily classified into

class III. The intent of this final rule is

to regulate these pre- and post-1976

devices in a consistent fashion. This

rulemaking does not affect requirements

for reagents that are subject to licensure

under the Public Health Service Act (the

PHS Act). This rulemaking also does not

affect reagents sold to nonclinical

settings, including those reagents sold

as components to manufacturers of

cleared or approved in vitro diagnostic

tests.

DATES: This rule is effective November

23, 1998.

FOR FURTHER INFORMATION CONTACT:

Steven I. Gutman, Center for Devices

and Radiological Health (HFZ–440),

Food and Drug Administration, 2098

Gaither Rd., Rockville, MD 20850, 301–

594–3084.

SUPPLEMENTARY INFORMATION:

I. Background

The the act (21 U.S.C. 201 et seq.), as

amended by the Medical Device
62244 Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations

Amendments of 1976 (Pub. L. 94–295)

(the amendments) and the Safe Medical

Devices Act of 1990 (Pub. L. 101–629),

established a comprehensive system for

the regulation of medical devices

intended for human use. Section 513 of

the act (21 U.S.C. 360c) established

three categories (classes) of devices,

depending on the degree of regulatory

controls needed to protect the public

health. The three categories of devices

are as follows: Class I, general controls;

class II, special controls; and class III,

premarket approval.

Devices that were in commercial

distribution before May 28, 1976 (the

date of enactment of the amendments),

are classified under section 360c of the

act after FDA has: (1) Received a

recommendation from a classification

panel, an FDA advisory committee, (2)

published the panel’s recommendation

for comment, along with a proposed

regulation classifying the device; and (3)

published a final regulation classifying

the device. A device that is first offered

in commercial distribution after May 28,

1976, and is substantially equivalent to

a device classified under this scheme, is

also classified into the same class as the

device to which it is substantially

equivalent.

A device that was not in commercial

distribution prior to May 28, 1976, and

that is not substantially equivalent to a

preamendments device, is classified by

statute into class III without any FDA

rulemaking proceedings. FDA

determines whether new devices are

substantially equivalent to previously

offered devices by means of the

premarket notification procedure in

section 510(k) of the act (21 U.S.C.

360(k)) and part 807 of the regulations

(21 CFR part 807).

FDA held a meeting of its

Immunology Devices Panel (the Panel)

on January 22, 1996, to seek expert

advice and public input on determining

the regulatory controls to be placed on

commercially marketed ASR’s. ASR’s

are reagents composed of chemicals or

antibodies that may be thought of as the

‘‘active ingredients’’ of tests that are

used to identify one specific disease or

condition. ASR’s are purchased by

manufacturers who use them as

components of tests that have been

cleared or approved by FDA and also by

clinical laboratories that use the ASR’s

to develop in-house tests used

exclusively by that laboratory. These inhouse developed tests (sometimes

referred to as ‘‘home brew’’ tests)

include those that measure a wide

variety of antibodies used in the

diagnosis of infectious diseases, cancer,

genetic, and various other conditions.

The Panel recommended that most

ASR’s be classified into class I because

the Panel believed that general controls

are sufficient to provide reasonable

assurance of the safety and effectiveness

of these ASR’s. The Panel’s

recommendation for classification was

based on the applicability of the general

controls usually associated with class I

products (e.g., registration, listing,

current good manufacturing practice

(CGMP), and medical device reporting),

as well as the inclusion of restrictions

on distribution, use and labeling. The

Panel determined that the primary risks

to health presented by ASR’s sold to

clinical laboratories are that they may be

manufactured with variable quality, or

be inappropriately labeled, or be used

by persons without adequate

qualifications. The Panel was also

concerned that practitioners ordering

the in-house tests made from ASR’s may

be unaware that the clinical

performance characteristics of these

tests have not been independently

reviewed by FDA. In addition, the Panel

identified a subset of ASR’s whose use

posed unique risks to public health

because of the substantial clinical

impact of the information generated

using these devices.

After the Panel meeting, FDA

published a proposed rule to regulate

ASR’s (61 FR 10484, March 14, 1996).

FDA received 31 comments on the

proposed rule from individuals,

manufacturers, professional societies,

and consumer and health associations.

The majority of the comments support

the regulations proposed by FDA. A

summary of the comments and FDA’s

response to them is provided below:

II. The Final Rule

A. General Approach

The final rule classifies or reclassifies

the majority of ASR’s as class I medical

devices. The final rule also exempts

these class I devices from the premarket

notification requirements of section

510(k) of the act. A small number of

ASR’s are being classified in class II or

III because the agency has determined

that additional requirements are

necessary for their safe and effective

use. Under the authority of section

520(e) of the act (21 U.S.C. 360j(e)), the

final rule restricts the sale, distribution

or use of all ASR’s subject to the rule.

FDA has determined that these

restrictions are necessary to provide a

reasonable assurance of the safety and

effectiveness of ASR’s, commensurate

with their potentiality for harmful effect

or the collateral measures necessary to

their use. The final rule restricts

ordering the use of in-house developed

tests using ASR’s to physicians or other

health care practitioners authorized by

applicable state law to access such tests.

The final rule also restricts the sale of

ASR’s to those clinical laboratories

regulated under Clinical Laboratory

Improvement Amendments of 1988

(CLIA) as qualified to perform high

complexity testing. In order to clarify

that the rule is intended to allow ASR’s

to be sold to State laboratories exempt

from CLIA certification, the language of

the regulation has been modified to refer

to laboratories ‘‘regulated’’ under CLIA

rather than ‘‘certified’’ under CLIA as

had been proposed. In addition, to

clarify that ASR’s may be sold to

Department of Veterans Affairs

(Veterans Affairs) laboratories not

covered by CLIA, the regulation has

been modified to include Veterans

Affairs laboratories regulated under

comparable laws; currently that law is

Pub. L. 102–139. The rule requires those

laboratories covered by the regulation to

provide a disclaimer with the results

obtained through use of in-house

developed tests incorporating these

ASR’s. The rulemaking does not affect

reagents sold to nonclinical settings,

including those sold as components to

manufacturers of approved or cleared in

vitro diagnostic tests. The rulemaking

does not affect requirements for reagents

that are subject to licensure under the

PHS Act.

B. Class II or III ASR’s

FDA has identified a small subset of

ASR’s that require class II special

controls to provide a reasonable

assurance of safety and effectiveness;

these are ASR’s used in blood banking

tests classified as class II devices where

the underlying tests have already been

cleared for marketing under section

510(k) of the act.

Class II blood banking tests fall into

two categories. One category consists of

blood banking tests required by FDA

that screen for diseases with a low

potential for transmission. The second

category consists of certain blood

banking tests used electively by blood

banks to screen for diseases that are

likely to be transmitted to subsets of

blood unit recipients known to be at

greater risk of infection. An example of

the second category is cytomegalovirus

serological reagents, which are used in

tests that aid in the diagnosis of diseases

caused by cytomegaloviruses. An

example of the first category is

treponema pallidum nontreponemal test

reagents, which are used in tests that aid

in the diagnosis of syphilis.

Class II ASR’s will be subject to

special controls that consist of the

following National Committee for
Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations 62245

Clinical Laboratory Standards (NCCLS)

documents: (1) ‘‘Specifications for

Immunological Testing for Infectious

Disease; Approved Guideline’’

(December 1994, NCCLS Document I/

LA18–A) and (2) ‘‘Assessment of the

Clinical Accuracy of Laboratory Tests

Using Receiver Operating Characteristic

(ROC) Plots; Tentative Guideline’’

(December 1993, NCCLS Document

KGP10–T) and the following FDA

guidance documents: (1) ‘‘Review

Criteria for Assessment of In Vitro

Diagnostic Devices for Direct Detection

of Mycobacterium spp.’’ (July 6, 1993)

and its ‘‘Attachment 1’’ (February 28,

1994); (2)‘‘ Draft Review Criteria for

Nucleic Acid Amplification-Based In

Vitro Diagnostic Devices for Direct

Detection of Infectious Microorganisms’’

(June 14, 1993); and (3) the Center for

Biological Evaluation and Research’s

‘‘Points to Consider in the Manufacture

and Clinical Evaluation of In Vitro Tests

to Detect Antibodies to the Human

Immunodeficiency Virus, Type I’’ (54

FR 48943, November 28, 1989). FDA

believes these special controls are

sufficient to ensure safe and effective

use of these ASR’s because these ASR’s

have previously been evaluated in tests

classified as class II and cleared by FDA.

Persons interested in obtaining the

documents previously referenced

should refer to section IV in this

document on ‘‘Access to Special

Controls.’’

In addition to the small subset of

ASR’s discussed above that have been

identified as class III, FDA also has

identified another small subset of ASR’s

for which class III premarket approval is

necessary to protect the public health.

These class III ASR’s are those whose

use poses unique risks because of the

substantial clinical and public health

impact of the information generated by

using these devices. This subset of

ASR’s are those incorporated in tests

intended to diagnose those contagious

diseases that are highly likely to be fatal

and where accurate diagnosis offers an

opportunity to mitigate the public

health impact of the condition or those

ASR’s incorporated in class III tests

intended to establish the safety of blood

and blood products, including genetic

tests intended to ensure the safety of the

blood supply. Examples of class III

ASR’s include ASR’s used in tests to

diagnose human immunodeficiency

virus/acquired immune deficiency

syndrome (HIV/AIDS) or tuberculosis.

Under § 864.4020(b) (21 CFR

864.4020(b)), those analyte specific

reagents that meet the class II or III ASR

definition will be reviewed as a

component of a test or kit. Because of

the serious health risks associated with

diseases diagnosed by tests utilizing

class II or III ASR’s, FDA believes that

meaningful safety and effectiveness

determinations require a review of the

performance of the entire test or kit,

including directions for use and

expected analytical or clinical

performance. Accordingly, FDA will

undertake premarket review of the

performance of the ASR and the test of

which it is a component to determine

the substantial equivalence or safety and

effectiveness of class II and III ASR’s. As

a result, it is expected that most class II

and III ASR’s will not be marketed as

independent components, separate from

the test. Where manufacturers of the

approved test or kit intend to market

these class II and III ASR’s

independently, without the other

components of the test, the restrictions

issued under section 520(e) of the act

will continue to apply. Cleared or

approved class II or III ASR’s that are

marketed independently of kits may be

sold only to in vitro diagnostic (IVD)

manufacturers, laboratories qualified to

do high complexity testing under CLIA,

or nonclinical laboratories for research

or other uses. These independently

marketed ASR’s must be labeled in

accordance with § 809.10(e) (21 CFR

809.10(e)), which has been amended to

include the following statement:

‘‘Except as a component of the approved

test (Name of approved test), analytical

and performance characteristics are not

established.’’

Although manufacturers of Class II or

III ASR’s marketed as independent

components are prohibited from making

statements regarding the analytical or

clinical performance of the ASR, they

may identify the approved test or kit.

Because the clinical laboratory is

accountable for the use of the

independently marketed ASR and its

performance as a part of a test, the

disclaimer required by § 809.30(e) (21

CFR 809.30(e) must be appended to the

results of in-house developed tests using

class II or III ASR’s just as it is required

with reports of results using class I

ASR’s. The same statement, of course,

would not be applicable or required

when test results are generated using the

test that was cleared or approved in

conjunction with review of the class II

or III ASR.

C. General Controls

The final rule requires biological or

chemical manufacturers and suppliers

of ASR’s to register with FDA and

provide FDA with a list of the ASR’s

they supply to laboratories for use in

developing in-house tests. The final rule

also requires manufacturers and

suppliers to conform to CGMP

requirements (part 820 (21 CFR part

820)), as applicable. The final rule

further requires manufacturers and

suppliers to comply with medical

device report (MDR) requirements (21

CFR part 803) and report to FDA

adverse events that may have been due

to the ASR’s. FDA believes that these

general controls address the risk to the

public health presented by ASR’s that

may be manufactured with variable

quality.

To reduce the burden on industry of

complying with CGMP’s, manufactures

and suppliers have until November 23,

1998 to comply with part 820.

D. General Purpose Reagents

FDA has amended the definition of

general purpose reagents to complement

and be consistent with the ASR

definition by adding language clarifying

the distinction between ASR’s and

general purpose reagents.

E. Genetics Testing

FDA does not intend, at this time, to

regulate ASR’s used in genetic testing

differently from other restricted class I

medical devices that are exempt from

premarket notification requirements.

The ASR regulations are drafted to

classify most ASR’s used to develop inhouse tests as class I devices because

FDA believes this degree of regulatory

control is commensurate with the need

to bring consistency to the manufacture

of these devices and to assure their

safety and effectiveness when used by

health and scientific personnel trained

in laboratory practices.

FDA considered identifying a subset

of ASR’s that are used to develop tests

intended for predictive genetic

diagnosis as ASR’s that pose unique

risks to the public health because of the

substantial clinical impact of the

information generated using these

devices. For the genetic tests currently

in use, FDA is aware that both the

genetic test and the ASR used in the

genetic test are developed by the

laboratory in-house. Because these

ASR’s are not being commercially

marketed independently of the tests,

they do not currently fall within the

scope of this regulation. Nonetheless,

FDA considered designating as class III

devices those ASR’s that would be

marketed independently for use in tests

intended for use in overtly healthy

people to identify a genetic

predisposition to a dementing disease,

or to fatal or potentially fatal medical

disorders (e.g., cancers or Alzheimer’s

disease), in situations where penetrance

is poorly defined or variable and latency

is 5 years or longer. However, after

reviewing the comments and currently
62246 Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations

available information, FDA has not yet

identified criteria that would logically

distinguish among genetic tests in order

to determine which have the requisite

impact to trigger more stringent

controls. FDA has determined that the

special issues related to genetic testing

or predictive genetic testing do not

warrant establishing a more stringent

degree of regulatory control over ASR’s

used in these tests at this time. FDA

believes that regulating most ASR’s as

restricted class I devices exempt from

premarket notification establishes

appropriate initial controls in the event

more stringent requirements are later

determined to be necessary for ASR’s

used in genetic tests.

FDA is aware of the public concern

and desire that the regulation of

products used in genetic testing be done

in a thoughtful and prudent manner. As

stated previously, FDA intends, with

this regulation, to establish appropriate

initial controls for ASR’s use in genetic

tests and to review agency policies

relating to many aspects of regulation of

genetic testing after FDA has had an

opportunity to evaluate anticipated final

recommendations from National

Institute of Health’s (NIH’s) Task Force

on Genetics Testing and other interested

parties. After this review, FDA may

propose additional regulation of genetic

tests.

F. Definition of an ASR

Most comments found FDA’s

proposed definition for an ASR to be

acceptable. However, FDA has decided

to make minor changes to clarify the

definition in response to some

comments. FDA has amended

§ 864.4020(a) to clarify that the

regulation only applies to reagents

intended for use in a diagnostic

application. FDA also has added the

term ‘‘ligand’’ to the categories of

materials that are within the definition

of ASR because ligands bind the

reagents to the analytes. Finally, FDA

has amended the definition to clarify

that binding between ASR’s and their

analytes may be through physical or

chemical means.

G. Disclaimer

Under § 809.30, FDA is requiring that

a disclaimer be appended by the

laboratory to the test report informing

the ordering practitioner of the test

results obtained from the test in which

the ASR was used. The statement will

say, ‘‘This test was developed and its

performance characteristics determined

by [Laboratory Name]. It has not been

cleared or approved by the U.S. Food

and Drug Administration.’’ FDA

believes the disclaimer clarifies the

regulatory status of the test in which the

ASR has been used, is consistent with

other in vitro diagnostic labeling, and

addresses the concern raised by the

Panel that practitioners ordering the

tests made from class I exempt ASR’s or

from class II or III ASR’s marketed

independently of an approved test may

be unaware that the clinical

performance characteristics of those

tests have not been independently

reviewed by FDA. The statement would

not be applicable or required when test

results are generated using the test that

is cleared or approved in conjunction

with review of the class II or III ASR. It

will be FDA’s responsibility to enforce

the disclaimer requirement.

H. Sale Restrictions

The final rule does not regulate the

sale of ASR’s to nonclinical laboratories.

FDA has amended § 809.30(a)(3) to

clarify that ASR’s may be sold for

nonclinical uses or uses not directly

related to patient care to academic and

other research laboratories as well as to

other nonclinical laboratories. It is not

the intent of the ASR regulations to

prevent the continued sale of ASR’s to

research institutions that are using these

devices for nondiagnostic testing.

I. Labeling Changes and Ordering

Restrictions

FDA has amended § 809.10(e)(9) to

clarify that labeling for class I exempt

ASR’s must include the statement,

‘‘Analyte Specific Reagent. Analytical

and performance characteristics are not

established.’’ For class II and III ASR’s,

FDA has amended § 809.10(e)(9) to

clarify that labeling must include the

statement ‘‘Analyte Specific Reagent.

Except as a component of the approved/

cleared test (Name of approved/cleared

test), analytical and performance

characteristics are not established.’’

Such labeling is consistent with other

IVD labeling and provides accurate

information to users and purchasers of

these products.

FDA has added § 809.10(f) to restrict

ordering in-house developed tests using

ASR’s to physicians or other health care

practitioners authorized by the law of

the State in which the test is being

offered. FDA believes that interpretation

of results from in-house developed tests

that use ASR’s requires the expertise of

a health care practitioner authorized by

the State to provide a reasonable

assurance of the safe and effective use

of commercially marketed ASR’s.

Because the performance characteristics

of the individual tests have not been

cleared or approved by FDA, consumer

use of such tests without the benefit of

the experience of a health care

professional would significantly

undermine safe and effective use of

these ASR’s.

III. Response to Comments

A. Comments Received in Response to

FDA’s Solicitation of Opinions on

Specific Issues

1. Genetic Testing

(Comment 1)

Several comments supported

regulating ASR’s used in genetic testing

as class I exempt devices. Those

comments asserted that:

(a) Use of genetic test results are better

addressed through regulations

pertaining to confidentiality of results,

discrimination based on genetic

information, and the qualifications of

genetic counselors and physicians, and

through standards and guidelines

established by professional

organizations rather than through more

stringent device controls.

(b) CGMP requirements, labeling

restrictions, as well as CLIA

requirements for qualifying laboratories

to perform high complexity testing

adequately, address FDA concerns about

the safety and effectiveness of ASR’s

used for such tests.

(c) More stringent classifications of

ASR’s used in genetic tests may hamper

the availability of genetic testing, which

would adversely affect the development

and practice of genetic medicine by

adding substantially to the time and

expense associated with test

development.

(d) Clinical laboratories have the

responsibility and expertise to validate

genetic tests, to establish standard

operating procedures so that tests can be

consistently replicated by technicians,

and to generate in-house reference

standards to test any new reagent lot for

specificity.

(e) ASR’s should not be singled out

for more stringent classification because

ASR’s are only one component of the

clinical assay; properties of the general

reagents used in the assay, such as ionic

strength, pH and concentration, as well

as conditions and procedures at the test

site, are also critical for determining

analytical specificity.

(f) Genetic tests are not fundamentally

different from other diagnostic

technologies.

(g) The proposed ASR category would

allow flexibility for medical decision

making but a system that attempts to

distinguish among different genetic

categories of testing, such as diagnostic,

carrier, population screening, or

prenatal diagnosis, would be unwieldy.

(h) Many ASR’s could be

unintentionally overregulated if a higher
Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations 62247

classification was established for this

group of ASR’s because a majority of

ASR’s could be used as ingredients in a

genetic test, even if they were not sold

for that use.

Other comments supported different

treatment for ASR’s used in genetic

tests:

(a) One comment suggested that it was

premature to regulate ASR’s composed

of human genetic products as class I

until the molecular basis of human

disease is better understood. Another

comment suggested that ASR’s should

be regulated as class III medical devices

if the practice of making in-house assays

of genetic tests directly available to

consumers becomes widespread or

problematic.

(b) Two comments recommended that

ASR’s used in genetic screening tests for

predictive purposes in apparently

healthy persons should be regulated

more strictly than class I, for example,

by requiring premarket notification.

(c) One comment proposed that ASR’s

whose only labeled indications are in

the area of genetic predisposition or in

prognostic situations with long latency

periods should be regulated as class II

or III devices.

(d) Two comments proposed

regulating ASR’s used in genetic testing

as class II devices. One comment

proposed special controls for these

ASR’s and no exemption from

notification. The second comment

would allow the sale of ASR’s to

laboratories without regard to

certification by CLIA.

(e) Because the clinical validity of

ASR’s may be difficult to establish, their

sensitivity and predictive value may not

be high, and the benefits they confer are

not proven, one comment recommended

that ASR’s used in genetic screening

tests for predictive purposes in

apparently healthy persons should be

available on an investigational basis

only. Another comment said they

should be available on an investigative

basis until clinical validity is proven,

and then they should be classified as

class III devices. Two comments

recommended that they should be

regulated as class III devices.

In general, FDA agrees with those

comments that support regulating ASR’s

used in genetic tests as class I exempt.

(See the discussion in section II.E. of

this document.) The regulations were

issued to apply to ASR’s as a category

of device, and most ASR’s can be used

in a variety of in-house developed tests.

At this time, FDA does not believe there

is a scientific basis to distinguish

between tests based on the use of DNA

and tests based on the use of other

proteins or substances, or between tests

based on the use of DNA and tests based

on the use of other molecular diagnostic

technologies. However, FDA recognizes

that there are special issues related to

genetic testing or predictive genetic

testing and that these issues may affect

the degree of regulatory control needed

to establish the safety and effectiveness

of these tests or the ASR’s used in their

development. As stated previously, FDA

intends to review its decision with

respect to regulatory control of genetic

testing after it has had an opportunity to

evaluate final recommendations from

NIH’s Task Force on Genetics Testing

and other interested parties.

FDA believes that this final regulation

will assure the quality of material being

used to develop in-house genetics tests.

When used as part of in-house

developed tests, the ASR regulations

restrict use of commercially marketed

ASR’s to tests that are ordered by an

authorized practitioner and to those

clinical laboratories regulated under

CLIA as qualified to perform high

complexity testing. Except when test

results are generated using the test that

was cleared or approved in conjunction

with review of the class II or III ASR,

FDA is also requiring that a disclaimer

be appended to the test report stating

that the clinical laboratory determined

and developed the test performance

characteristics and that the test that

incorporated the ASR has not been

cleared or approved by FDA. FDA

believes these restrictions address many

of the concerns raised by those

comments supporting more stringent

regulation of ASR’s used in genetic

testing. The issuance of these

regulations does not preclude FDA from

reevaluating in the future whether

additional controls may be needed for

genetics testing or for ASR’s used in

such tests. FDA will reevaluate whether

additional controls may be needed to

provide an appropriate level of

consumer protection if further

developments in this area result in

significant uses of ASR’s in genetic

assays or other IVD tests offered overthe-counter (OTC).

(Comment 2)

One comment stated that issues raised

by predictive testing which yields

information about the potential future

health status of the patient and his or

her blood relatives have been addressed

by policy statements from professional

groups. This comment asserted that the

most practical approach to oversight

and regulation of genetic testing would

build on the existing system of

professional society standards, using a

system that creates either incentives for

compliance or disincentives for

noncompliance. The comment also

stated that reliance on voluntary

professional standards would minimize

costs to Government agencies and avoid

burdening compliant manufacturers

with unnecessary regulation. Another

comment recommended that regulation

of human genetic testing should be

considered separately from decisions

regarding the appropriate classification

and regulatory controls applied to

ASR’s.

As stated previously, FDA recognizes

that there are special issues related to

genetic testing or predictive genetic

testing. Implementation of a system

based on professional standards for

oversight of genetic testing is one option

for addressing these issues. FDA does

not believe the regulatory steps being

taken in this final rule overly burden

manufacturers or preclude other types

of controls in the future, including

systems based on the principles

described in this comment.

2. Nucleic Acids

(Comment 3)

Several comments agreed with FDA’s

proposal to include human nucleic

acids within the definition of ASR’s.

Those comments stated that: (a) It

would be inconsistent to exclude

human nucleic acids; (b) human nucleic

acids are essential for good patient

management where no FDA approved

alternative test can substitute; (c) the

scientific basis for nucleic acid

hybridization and amplification

techniques utilizing oligonucleotide

ASR’s have been known for many years

so that adherence to CLIA regulations

should be sufficient regulation; (d)

because factors affecting test

performance, reliability, and accuracy of

test results are assay dependent and not

disease dependent, all ASR’s should be

regulated similarly as class I devices

exempt from premarket notification; (e)

the ongoing refinement of reagents for

diagnosis of susceptibility genes

required by the practice of medicine is

facilitated when ASR’s are required only

to meet a minimum number of

regulatory requirements; (f) the

availability of nucleic acid probes for

use in the practice of medicine will be

facilitated if these nucleic acids are

regulated as class I devices exempt from

the premarket notification requirement;

and (g) like other ASR’s, human nucleic

acids can be used in disease staging.

Several comments supported the

exclusion of the word ‘‘nonhuman’’ to

modify nucleic acids in the ASR

definition, stating that it would be

virtually impossible to distinguish

between a nucleic acid synthesized in

the laboratory and a human nucleic

acid, and that human nucleic acids are
62248 Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations

not the only category of ASR capable of

being used in genetic tests. One

comment expressed concern that FDA

has appeared to misunderstand the

panel’s intent, which was to exclude

human nucleic acids because they are

most often used to directly identify

genetic material or gene products. FDA agrees with the comments that

support including human nucleic acids

in the ASR definition. FDA appreciates

the basis for the concern raised by the

comment about the intent of the panel

recommendation, but remains

concerned about the broad nature of

such an exclusion. Consequently, the

definition of ASR’s in the final rule

includes human nucleic acids. As

discussed earlier, at a future date, FDA

may reevaluate whether additional

controls over genetic tests are

appropriate.

3. Analyte Specific Reagent

(Comment 4)

Several comments supported the use

of the term ‘‘analyte specific reagent’’

and no comment suggested an

alternative.

Accordingly, FDA has retained this

term in the final regulation.

4. Disclaimer

(Comment 5)

Several comments agreed with the

proposed disclaimer, noting that it

clarifies the regulatory status of ASR’s,

it is consistent with the current practice

of labeling research or investigational

IVD’s, and it provides an incentive for

laboratories to have their assays

approved or cleared. Several comments supported having a

disclaimer, but would like it to contain

more information, including that the

clinical performance of the test has not

been established, that neither the

laboratory test nor the procedures used

to obtain the results have been reviewed

by FDA, and that the ASR manufacturer

is accountable for the ASR.

Other comments suggested that the

disclaimer be deleted, or, at a minimum,

amended to read that the laboratory

assay used to report these results has

been validated in accordance with the

requirements of CLIA. One comment

would amend the disclaimer to read as

follows:

The reagents used in this test are

regulated by the Food and Drug

Administration (FDA) under the general

controls of the Food, Drug, and

Cosmetic Act (FDC Act). The regulations

that implement the FDC Act require

compliance with current good

manufacturing practices (CGMP),

accurate labeling and adverse event

reporting, among others. The

distribution of these reagents is limited

to manufacturers of in vitro tests,

laboratories qualified to perform high

complexity testing and forensic and

underwriter laboratories. This test was

validated in accordance with the

provisions of the Clinical Laboratory

Improvement Amendments (CLIA’88).

The program is managed by another

federal agency, the Health Care

Financing Administration (HCFA).

(Laboratory Name) was certified/

recertified by HCFA on (date) as a high

complexity laboratory that is in

compliance with CLIA regulations.

Three comments opposed requiring

any disclaimer, claiming it has no

impact on the final diagnosis and is an

intrusion on the process of medical

interpretation. One of these comments

suggested that it would be more

reasonable to require the laboratory

director to provide interpretive

reporting to the physician.

FDA has considered the comments

and has determined to require the

disclaimer discussed in the proposed

rulemaking. FDA believes that the

disclaimer is sufficiently clear to

communicate that the test that used the

ASR was developed, and its

performance characteristics defined, by

the laboratory without FDA review.

FDA believes this statement clearly

communicates to health care providers

the regulatory status of the in-house test

that has used the ASR. FDA believes

this labeling requirement is necessary to

address the concern raised by the Panel

that physicians may not be aware that

the results of the testing they order

using ASR’s are generated by tests that

have not been independently reviewed

by FDA. Rather than being an intrusion

on medical interpretation, the required

statement ensures that health care

providers have additional information

upon which to make independent

judgments. This labeling requirement

would not be applicable or required

when test results are generated using the

test that was cleared or approved in

conjunction with review of the class II

or III ASR. FDA does not believe a more

detailed or lengthy statement is

necessary.

B. General Comments

(Comment 6)

Several comments supported the

regulation of ASR’s as class I devices,

exempt from premarket notification

requirements in section 510(k) of the

act. These comments stated that: (a) The

CLIA regulations regarding in-house

modification of materials or methods are

adequate to protect the health and wellbeing of patients without increasing the

regulatory burden on manufacturers and

laboratories or overloading FDA’s

already encumbered review process by

classifying ASR’s in a more stringent

category; (b) in-house modification of

materials and methods falls within the

scope of the practice of medicine, and

a more stringent classification would

hamper the ability to provide quality

medical services and care to patients,

such as diagnostic work performed by

pathologists; (c) stringent regulation of

in-house modified or developed

materials and methods would constrain

the development of new and better

technologies and the improvement of

existing IVD technologies; and (d) a

substantial and appropriate measure of

control is gained by the regulation

announced in the proposed rule.

As recommended in these comments,

FDA is finalizing the class I exempt

classification as the classification for

most ASR’s.

(Comment 7)

One comment expressed concern that

the proposed regulation would put

companies that have made the

investment to obtain clearance of

510(k)’s for class II antibodies at a

competitive disadvantage if antibodies

that are currently classified as class II

are reclassified as class I devices exempt

from premarket notification.

FDA disagrees with this comment.

Manufacturers that have submitted or

intend to submit antibodies for review

as class II test systems would be allowed

to market those devices with clear

intended uses and indications for use,

instructions for use, and appropriate

definition of performance parameters.

Manufacturers of class I exempt ASR’s

will be required to limit their labeling

to a description of the identity and

purity (including source and method of

acquisition) of the ASR in addition to

standard information already required

for general purpose reagents (e.g., net

weight; storage instructions). Sale of

class I exempt ASR’s is also restricted in

accordance with other restrictions listed

in 21 CFR 809.30(b), while

manufacturers of class II test systems

cleared by FDA would be allowed to

market those devices without regard to

the restrictions in 809.30.

(Comment 8)

One comment questioned whether

classification of class III ASR’s by the

type of test for which it is to be used

will create a quagmire of regulations,

resulting in numerous exceptions to the

class I status, confusion about how

ASR’s that can be used in multiple tests

will be regulated, and the difficulty of

distinguishing one fatal illness, such as

HIV/AIDS, from another, such as herpes

encephalitis.

FDA believes that through a narrow

definition of the class II and III

identification, the exceptions to the

general ASR classification have been

limited to a manageable number. Under

the final rule, exceptions to the ASR

class I exempt classification are analytes
Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations 62249

used in developing a test intended for

use in the: (a) Diagnosis of a contagious

condition that is likely to result in a

fatal outcome and where prompt

accurate diagnosis offers the

opportunity to mitigate the public

health impact of the condition; (b)

screening of a condition for which FDA

has established a recommendation or

requirement for the use of the test in

safeguarding the blood supply or

establishing the safe use of blood and

blood products (e.g., hepatitis or tests

for identifying blood groups); or (c)

screening for blood banking when

screening test has been classified as a

class II device. Currently, FDA believes

that ASR’s used to test for evidence and

monitoring for levels of HIV/AIDS and

tuberculosis (TB) are examples that

would fall within the class III exception,

and reagents used in the diagnosis of

diseases caused by cytomegaloviruses

and treponema pallidum nontreponemal

test reagents which aid in the diagnosis

of syphilis fall within the class II

exception. Most blood banking tests fall into

class III and some into class II. Class II

blood banking tests fall into two

categories. One category consists of

blood banking tests required by FDA to

screen for diseases with a low potential

for transmission, e.g., syphilis. The

second category consists of certain

blood banking tests used electively by

blood banks to screen for diseases that

are likely to be transmitted to subsets of

blood unit recipients known to be at

greater risk of infection, e.g.,

cytomegalovirus. Because these blood

banking tests have previously been

classified into class II, FDA has

determined that special controls are

sufficient and that the submission of a

premarket approval application (PMA)

associated with a class III device is not

necessary for the ASR used in the test.

(Comment 9)

One comment suggested that only

those ASR’s with the lowest risk factor

for generating false results of little

consequence should be classified as

class I, and that the others should be

classified as class II or III. The comment

reasoned that the reliable, reproducible

performance of a diagnostic test is

dependent upon the entire integration of

the test system. The comment also

stated that while laboratories qualified

to do high complexity testing have

experience in utilizing and evaluating

test systems developed by

manufacturers, these laboratories do not

have expertise in developing in vitro

diagnostic tests. The comment noted

that CLIA does not require the

validation of diagnostic tests systems by

rigorously controlled clinical trials to

establish expected values and

performance characteristics. Such trials

are not required by CLIA but could be

required by FDA if these tests were

placed in class II or III. FDA has considered this and related

comments and appreciates the concerns

raised about the development of inhouse tests and the current marketing of

test services based on tests that have not

been reviewed independently for safety

and effectiveness. FDA believes that

clinical laboratories that develop such

tests are acting as manufacturers of

medical devices and are subject to FDA

jurisdiction under the act. However,

FDA recognizes that the use of in-house

developed tests has contributed to

enhanced standards of medical care in

many circumstances and that significant

regulatory changes in this area could

have negative effects on the public

health. For these reasons, FDA declines

to accept the suggestion that all inhouse developed tests be classified as

class II or III medical devices. FDA

views this final rule as a reasonable

regulatory step at this time and an

important contribution to assuring that

the primary ingredients of most inhouse developed tests are manufactured

properly, used by trained professionals,

and labeled accurately. The focus of this rule is the

classification and regulation of ASR’s

that move in commerce, not tests

developed in-house by clinical

laboratories or ASR’s created in-house

and used exclusively by that laboratory

for testing services. The regulation

restricts the sale of ASR’s to a particular

type of laboratory and FDA believes this

restriction supports the safe and

effective use of these ASR’s. FDA

believes that CLIA regulated laboratories

qualified to perform high complexity

testing have demonstrated expertise and

ability to use ASR’s in test procedures

and analyses. In addition, the disclaimer

being required by this rule will provide

physicians with more complete

information to better understand the

basis of test development and to

evaluate the information generated by

the laboratory using the ASR. Nevertheless, FDA understands that

the use of ASR’s to develop in-house

tests raise questions about the safety and

effectiveness of the tests that

incorporate these ASR’s. FDA has

determined that certain types of testing

raise public health concerns that require

more stringent regulation of the ASR’s

that are the main ingredients of those

tests: testing for highly contagious and

fatal diseases and testing that protects

the safety of the blood supply require

different and additional review. As

proposed, FDA is now classifying the

ASR’s associated with such testing into

class III. In addition, FDA is classifying

into class II those ASR’s that are used

in blood banking tests which previously

have been classified into class II. These

class II and III devices will be reviewed

in association with the test that is

incorporating the ASR so that FDA can

assure a level of safety and effectiveness

that is commensurate with the intended

use of the ASR. In addition, ASR’s and

tests using ASR’s that meet the

definition of a biologic remain subject to

licensure under the PHS Act.

Finally, FDA notes that the comment

misunderstood the requirements under

CLIA with respect to tests in the waived

category. Under CLIA, manufacturers

are required to submit studies to

demonstrate that the statutory criteria

for waiver are met, and any waived test

must either be approved/cleared by FDA

for home use or be simple, easy to

perform, and essentially error free. The

Centers for Disease Control and

Prevention (CDC) is responsible for

implementing the categorization

provision of CLIA, including waived

States.

(Comment 10)

One comment expressed concern that

FDA has not fully discussed regulating

moderate risk products and suggested

that the level of sophistication of

diagnostic technology requires more

than two categories.

Although the final rule establishes

three classes of ASR’s, FDA disagrees

that most moderate risk ASR’s require

additional regulation. FDA believes that

the classification of most ASR’s as

restricted class I devices in conjunction

with existing CLIA regulations and

professional organization’s standards

applicable to laboratories qualified to do

high complexity testing is adequate for

regulating ASR’s used in both low and

moderate risk in-house assays. In

addition, FDA has identified a small

subset of ASR’s used in class II blood

banking tests that require special

controls to provide a reasonable

assurance of safety and effectiveness

and that will be regulated as class II

devices. The regulation represents an

incremental regulatory change and does

not preclude future regulatory activity

by FDA or other Federal or professional

groups involved in oversight of

laboratory activities from developing

mechanisms to improve the quality of

laboratory practice or test production.

(Comment 11)

Several comments objected to any

FDA regulation of ASR’s. One of these

suggested that FDA should work with

HCFA to amend HCFA’s regulation of

clinical laboratories if changes in

current regulation of home brews are
62250 Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations

necessary, claiming that FDA’s

regulation in this area would only

increase the administrative costs of

medical care. Another comment stated

that: (a) There is an absence of safety or

effectiveness concerns in ASR use; (b)

regulating ASR’s increases the burden

on FDA’s scarce resources and facilities;

(c) CLIA regulation is sufficient; and (d)

the proposed rule does not target the

party best suited to address issues of

analytical validity, which is the

laboratory preparing the in-house test.

Another comment expressed concern

that the proposed rule encourages inhouse production of ASR’s. Another

comment suggested providing guidances

rather than regulating by rulemaking.

FDA disagrees with these comments.

FDA intends that this final rule,

developed with input from HCFA and

CDC, complement existing regulations

issued under CLIA. FDA’s rule

establishes a basic requirement that

manufacturers of ASR’s for use in

clinical laboratories comply with

appropriate CGMP’s. CGMP procedures

and controls are designed to ensure high

quality devices. FDA believes that high

quality ASR’s are likely to lower costs

of developing and maintaining test

systems at individual laboratory sites

and to decrease, rather than increase,

total medical costs.

FDA regards regulating ASR’s using

general controls and exempting them

from the premarket notification

requirements as a minimal burden and

an appropriate level of regulation for

devices that pose less safety or

effectiveness concerns than devices

marketed as test systems or test kits. In

keeping with this approach, this rule

addresses quality and identity of the

ASR’s and does not address analytic

validity of the devices. FDA does not

expect this regulation to independently

increase efforts by laboratories to

develop ASR’s in-house. FDA believes

that the in-house development of ASR’s

is driven by research goals, and is not

a practice that grows in response to

regulatory efforts. Finally, while it may

be necessary for FDA to develop

guidances concerning ASR’s in the

future, FDA believes that establishing a

classification for ASR’s through

rulemaking is the appropriate

mechanism to ensure consistent

regulation of these devices for their

manufacturers and users.

(Comment 12)

One comment suggested that the

Panel’s recommendation would unfairly

burden the manufacturer of the ASR and

that the clinical laboratory was the best

party to ensure that the appropriate

restraints are placed on interpretation of

a diagnostic test through a disclaimer

provision.

FDA agrees in part with the comment.

FDA intends to minimize the regulatory

burden on ASR manufacturers by

regulating most ASR’s as class I devices

exempt from premarket notification.

The final rule requires that a disclaimer

be appended to the test report by the

laboratory that uses the ASR. That

statement will inform the ordering

practitioner that: ‘‘This test was

developed and its performance

characteristics determined by

(Laboratory Name). It has not been

cleared or approved by the U.S. Food

and Drug Administration.’’ The

statement would not be applicable or

required when test results are generated

using the test that was cleared or

approved in conjunction with review of

the class II or III ASR.

(Comment 13)

One comment expressed concern

about regulating the ASR ingredient,

rather than the final test product,

claiming that most clinical laboratories

will not establish the clinical

performance of a diagnostic product via

properly controlled and population

representative clinical trials.

FDA understands the concern raised

by this comment but disagrees that

regulation of ASR’s will not be useful

and that regulation of all in-house

developed tests is appropriate at this

time. As discussed previously, FDA has

concluded that its regulation of ASR’s

will contribute to consistency and

quality in their manufacture and that

the requirement that the laboratory

using the ASR explain the regulatory

status of the test in which it was used

will increase the information available

to physicians ordering these tests.

Development of in-house laboratory

tests is a complex process in which

diagnostic performance may be assessed

either through the medical practice

associated with a given laboratory or

scientific literature. Although the types

of trials performed in support of these

tests are likely to be variable,

laboratories will be responsible for both

the quality and interpretation of results

generated from these tests.

(Comment 14)

One comment questioned whether

FDA has the resources to require CGMP

compliance from all ASR manufacturers

and prevent the inappropriate use of

‘‘research use only’’ labeling.

FDA believes it does have resources to

enforce the requirements established by

this regulation. The regulation requires

all ASR manufacturers to follow general

controls and, as with other FDA

regulations, it is primarily the

responsibility of the manufacturer to

comply with the regulations pertaining

to ASR’s. FDA intends to monitor the

level of compliance through inspections

and, where necessary, take enforcement

actions. FDA also expects that the

clinical laboratory and physician

community will join manufacturers in

encouraging compliance; laboratories

purchasing these ASR’s and physicians

ordering tests using these ASR’s will

now expect them to be produced

consistently in accordance with

appropriate CGMP’s.

(Comment 15)

One comment suggested regulating

the ASR by the same classification as

the final assay.

FDA disagrees with this comment. A

single class I ASR may be potentially

used in multiple different versions of a

final assay, which are developed and

run by individual clinical laboratories.

Basing the regulation of every class I

ASR on the final assay developed and

run by individual clinical laboratories,

therefore, would be problematic. FDA

believes that existing mechanisms for

laboratory oversight under the mandate

of CLIA are sufficient in most cases to

assure proper test control.

(Comment 16)

One comment requested information

on how the proposed rule relates to the

immunohistochemical (IHC) regulation

and the definition of IHC’s, the

Compliance Policy Guide (CPG) for the

Distribution of Research and

Investigational Use Products, and other

classification actions currently

underway.

Depending on their labeling and

intended use, devices for use as IHC

stains could be marketed under a variety

of options. When an IHC is developed

as a kit or system for ‘‘in vitro diagnostic

use’’ (with a proposed intended use,

indications for use, instructions for use,

and performance characteristics), it

would be subject to review as a class I,

II, or III device according to intended

use as outlined in the proposed IHC

regulation (61 FR 30197, June 14, 1996).

When an IHC is developed and

marketed as an ASR (intended for ASR

use only, with no instructions for use,

and no defined performance

characteristics), it would be subject to

general controls and restrictions

established by this final regulation but

would be exempt from premarket

review. When an IHC is developed and

used only for ‘‘research use’’ or

‘‘investigational use,’’ it would be

subject to appropriate labeling only with

no requirement for premarket review or

compliance with the general controls or

restrictions of this ASR regulation.

In August of 1992, FDA invited

comment on a draft CPG entitled
Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations 62251

‘‘Commercialization of Unapproved In

Vitro Diagnostic Devices Labeled for

Research and Investigation,’’ which was

intended to clarify the regulation of

devices ‘‘for research use’’ or ‘‘for

investigational use’’ and to describe

FDA’s enforcement policy concerning

research or investigational IVD’s that are

being illegally commercialized for

diagnostic or prognostic purposes. Any

final CPG issued on this subject will be

consistent with the ASR regulations.

(Comment 17)

One comment recommended that

FDA create a task force to assist FDA in

further delineating and defining issues

raised in the proposed rule.

FDA believes that the comments

submitted in response to the proposed

rule provide the assistance FDA sought

in delineating and defining the issues

raised in the proposed rule and believes

that it is unnecessary to institute an

additional procedure at this time to

address these issues. Where products

pose new or unusual risks, FDA may

seek assistance in classifying the

products.

C. Adverse Event Reporting

(Comment 18)

One comment objected to the

requirement that the ASR supplier be

required to report adverse events and

asserted that it would add an

unnecessary step to the reporting

process because ASR suppliers depend

on the clinical laboratory to inform

them of the occurrence of an adverse

event.

FDA disagrees with this comment.

This requirement is consistent with the

medical device reporting regulations in

part 803, which require device user

facilities and manufacturers to report

deaths and serious injuries to which a

device has or may have caused or

contributed, and to establish and

maintain an adverse event file. Under

these regulations, the burden for

reporting adverse events is shared by

both health care providers and

manufacturers. If a number of events

become associated with a particular

ASR, it is the manufacturer who is

likely to be in the best position to

investigate the cause of the adverse

events and to take corrective action, if

necessary.

D. ASR Definition in § 864.4020(a)

(Comment 19)

One comment expressed concern that

the proposed definition of ASR’s would

adversely impact basic research, noting

that it included every polyclonal or

monoclonal antibody specific to a

human antigen and every

oligonucleotide primer used in

polynerase chain reaction (PCR), reverse

transcription or labeled for use in

detecting hybridization, including those

whose primary or entire use is in basic

research.

FDA does not intend to have this

regulation apply to basic research and

has amended the definition of ASR

§ 864.4020(a) to clarify that the

regulation applies only to reagents

intended for use in a diagnostic

application.

(Comment 20)

One comment would add the term

‘‘ligand’’ to the proposed ASR

definition, stating it is the ligand which

binds to the categories of materials that

are proposed to be within the ASR

definition. Two comments would add

‘‘diagnostic’’ to the definition to clarify

that an ASR is only intended for

diagnostic use. One comment suggested

amending the ASR definition to read

‘‘specific binding or chemical reaction,’’

noting that binding between ASR’s and

analytes is often through physical

means and that ASR’s may also react

chemically with analytes.

FDA agrees with the suggested

clarifications and has modified the

definition accordingly.

(Comment 21)

One comment stated that the chemical

or biological source of a reagent should

not preclude it from being identified as

an ASR.

FDA agrees with this comment and

believes that the definition of ASR’s

supports this concept.

E. Blood Supply

(Comment 22)

Two comments supported the

regulations of ASR’s used in tests

intended to safeguard the blood supply

as class III devices.

FDA agrees with these comments and

will continue to classify ASR’s used in

tests intended to safeguard the blood

supply as class III devices because of the

serious health risks associated with

their use in that setting. As discussed

previously, ASR’s used in tests that

previously have been classified in class

II, will be class II, rather than class III.

ASR’s and tests using ASR’s that meet

the definition of a biologic remain

subject to licensure under the PHS Act.

(Comment 23)

One comment questioned whether it

is consistent to apply class II or III and

other regulatory requirements to

manufacturers of ASR’s used in blood

banking tests and suggested it would be

more appropriate to have the regulatory

focus be on the developer of the inhouse assay.

Although FDA has concluded that

class I is an appropriate classification

for most ASR’s, FDA believes that

regulation of the blood supply requires

maximum assurance of safety, and that

ASR’s used in tests intended to

safeguard the blood supply require a

different and more stringent level of

control. Accordingly, ASR’s used for

tests that are intended to assure the

safety of the blood supply will be

reviewed in association with the test

that is going to incorporate that ASR.

The concern of the comment is

addressed, therefore, because the test

will be reviewed in order to establish

that the ASR can be used safely and

effectively. FDA’s Center for Biologic

Evaluation and Research (CBER) will

continue to take the lead in the review

of such products and should be the

point of contact for manufacturers of

ASR’s that are intended to be used in

tests relating to the safety of the blood

supply. These tests remain subject to

licensure under the PHS Act.

(Comment 24)

One comment expressed concern that

labeling test results using ASR’s as not

having been reviewed by FDA would

restrict the use of valuable reagents used

in immunohematology and suggested

that the regulation of blood bank/

immunohematology tests be specifically

addressed by a panel of expert

serologists.

FDA does not believe that the

situation suggested by the comment is

likely to occur. CBER has not licensed

any biologic that is used in tests

intended to safeguard the blood supply

without reviewing and approving the

test that will incorporate that biologic.

This policy will not be affected by this

final rule. Under this policy, an ASR

should not be incorporated into a home

brew test designed to protect the safety

of the blood supply unless that test has

been approved by FDA or is being

investigated under an effective

investigational new drug application.

Because these ASR’s would only be

used in association with tests that have

already been approved, the disclaimer

would not be applicable or required

when test results are generated using the

test that was cleared or approved in

conjunction with review of the class II

or III ASR.

F. Certification

(Comment 25)

Several comments recommended that

FDA not require ASR suppliers to

certify that sales comply with the

proposed sale restrictions, claiming that

such certification would be a

recordkeeping burden.

These comments appear to have

misread the rule. There was no

certification requirement in the
62252 Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations

proposed ASR regulation and none has

been included in the final rule. The ASR

rule does not require ASR suppliers to

certify that sales comply with the

proposed sale restrictions.

G. CGMP’s

(Comment 26)

Several comments objected to the

application of CGMP’s where ASR’s are

rare reagents made only once or so

infrequently that CGMP’s cannot be

properly applied, or where ASR’s are

reagents made in an academic or

research setting, or by very small

companies. One comment suggested

that acceptance specifications

developed by individual laboratories for

key ingredients and test performance

criteria would determine an individual

laboratory’s standard for acceptability

for manufacturing those ASR’s.

In response to these comments, FDA

notes that manufacturers are not

required to follow CGMP’s for reagents

made and used within academic or

research settings. For rare or

infrequently made ASR’s, FDA intends

to apply only those provisions of the

CGMP’s as are appropriate to ensure the

quality and purity of the ASR’s being

marketed for clinical applications.

However, the size of a company that

commercially markets ASR’s will not

exempt that manufacturer from

compliance with appropriate CGMP’s.

H. Economics

(Comment 27)

One comment stated that carefully

controlled and documented

performance of IVD tests will curb

medical care costs by contributing to

more specific diagnosis and more

selective patient management. This

comment suggested that FDA’s

regulation of ASR’s is not stringent

enough and that FDA should regulate

in-house developed tests the same way

FDA regulates other IVD’s.

FDA believes that applying general

controls to the majority of ASR’s used

to develop in-house tests is, in

conjunction with CLIA certification of

the laboratory, the appropriate degree of

regulatory control. As discussed

previously, FDA appreciates the

concerns that have been raised about inhouse developed tests that are not

reviewed independently. If future

developments in laboratory technologies

or marketing of in-house developed tests

indicate that additional regulation is

necessary to provide an appropriate

level of consumer protection, FDA may

reevaluate whether additional controls

over in-house developed tests are

warranted.

(Comment 28)

Several comments expressed concern

that the proposed regulations will

increase the cost of diagnostic tests and/

or decrease the availability of those

reagents that are low use/low revenue

products. The comments suggested that

large companies will pass along the

increased costs to consumers and that

small companies will be unable to

comply because the cost is prohibitively

expensive. A comment also questioned

what the regulatory impact would be on

a clinical laboratory that both

manufactures the ASR and uses the ASR

in an in-house test.

FDA believes that the ASR regulations

are a minimal regulatory burden and

should improve the assurance of quality

for purchasers of ASR’s for use in test

development without significantly

increasing costs. In response to the

concern that this regulation will

eliminate the manufacture of low use

ASR’s, FDA notes that it has recently

published regulations for humanitarian

device exemption procedures (61 FR

33232, June 26, 1996) which could be

applied to low use/low revenue

products to prevent disruption of this

important market. As explained

previously, ASR’s developed in-house

and not marketed to other laboratories

generally would not be subject to the

ASR requirements established under the

final rule. However, as noted

previously, ASR’s and tests

incorporating ASR’s that meet the

definition of a biologic that are intended

to protect the blood supply will remain

subject to licensure under the PHS Act.

I. Sales Restriction to CLIA Regulated

Laboratories That Perform High

Complexity Testing

(Comment 29)

One comment objected to the

restriction of sales of ASR’s to CLIA

laboratories that perform high

complexity testing, stating that such

laboratories may lack training and/or

experience in such tests. The comment

suggested that the sale of ASR’s should

be restricted to a laboratory’s area of

testing, rather than complexity of

testing. Another comment stated that

CLIA’88 does not provide assurance of

safety and efficacy of tests because it

does not require assessment of a test’s

clinical validity or utility. Several

comments supported the proposed

restriction of sales to laboratories

qualified to perform high complexity

testing under CLIA because CLIA

established minimum standards for

proficiency testing, quality assurance,

quality control, and personnel. FDA believes that restriction to a

laboratory regulated under CLIA or

comparable laws regulating Veterans

Affairs laboratories as qualified to

perform high complexity testing will

ensure that these devices are handled in

a setting that complies with the most

stringent Federal regulatory standards

for laboratory practice. FDA believes

that these laboratory practice standards

are a more appropriate regulatory

distinction than areas of speciality,

which may often overlap and are

difficult to define.

FDA recognizes that CLIA does not

require laboratories to assess the clinical

validity of in-house developed tests. Nor

do FDA’s ASR regulations address the

clinical validity of these tests. The

purpose of restricting the sale of ASR’s

to laboratories qualified to perform high

complexity testing under CLIA is to

make certain that these devices are

being handled by individuals whose

training and experience are likely to

assure the safe and effective use of the

ASR’s themselves. FDA currently

believes that regulating the active

ingredients of in-house developed tests

should provide an appropriate level of

regulation to protect the public health.

However, the ASR regulations do not

preclude FDA or other Federal agencies

from taking other measures authorized

by law to assure assessment of a test’s

clinical validity or utility if such

measures are needed. As stated

previously, at a future date, FDA may

reevaluate whether additional controls

over the in-house tests are warranted to

provide an appropriate level of

consumer protection.

(Comment 30)

One comment asked how ASR

manufacturers can identify laboratories

qualified to perform high complexity

testing and whether ASR suppliers

would be required to re-assess a

laboratory’s classification on an annual

basis.

The ASR regulations require ASR

manufacturers to label and market

ASR’s appropriately. FDA is allowing

manufacturers and suppliers until

November 23, 1998 to deplete their

current stock of lables before requiring

compliance with the labeling

requirements. While the ASR

regulations do not require ASR

suppliers to certify sales to laboratories

qualified to perform high complexity

testing, such voluntary certification

programs may be one way to ensure

proper marketing of ASR’s. Information

concerning whether a particular

laboratory is qualified to perform high

complexity testing may be obtained by

calling the State survey agency in the

State where the laboratory is located.

(Comment 31)

Two comments stated that CLIA does

not certify or regulate European clinical
Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations 62253

laboratories. The comments suggested

that, in foreign countries, ASR’s be sold

in accordance with the laws of that

country.

FDA agrees and does not expect the

ASR regulations to affect the marketing

of ASR’s to laboratories or suppliers in

foreign countries.

J. Research

(Comment 32)

One comment asked whether ASR’s

could be sold to universities doing pure

research, and if so, would such ASR’s

require a separate research use only

(RUO) label.

ASR’s can be sold to universities

doing research and FDA has amended

809.30 to clarify this point. ASR’s and

products labeled ‘‘for in vitro diagnostic

use’’ can be used for research purposes

so an additional label would not be

necessary in those circumstances.

However, products that have not been

manufactured in accordance with

CGMP’s and are labeled ‘‘for research

use only’’ cannot be marketed under the

ASR classification or used by

laboratories to develop clinical

diagnostics.

K. Contagious Fatal Diseases

(Comment 33)

Two comments supported the

regulation of ASR’s used in tests

intended for use in the diagnosis of

potentially fatal contagious diseases as

class III devices. Several comments

objected to classifying such ASR’s as

class III, stating that: (a) Stricter

regulation will impair the ability of the

clinical laboratories to respond rapidly

to outbreaks of new or emerging

infectious diseases, (b) the patient

population is small, (c) the proposed

regulation of other ASR’s provides

sufficient regulation, and (d) it will

cause confusion in a variety of

situations, for instance, where the

disease typically is not fatal, but

occasionally may cause fatalities, or

where an ASR may be used for multiple

purposes, ranging from screening

procedures to monitoring treatment or

progression of disease, or where an ASR

is used for the diagnosis of both

infectious and noninfectious diseases.

One comment suggested that it would

be more appropriate to require

premarket notification for these ASR’s

or to regulate them as class II devices

that require premarket notification and

special controls, rather than classify

these ASR’s as class III.

FDA does not believe that regulating

this limited category of ASR’s as class

III devices will confuse the industry or

interfere with laboratory development of

tests. ASR’s will be identified as class III

devices only when they are intended to

be used either in tests that establish or

safeguard the safety of the blood supply

or in tests that diagnose contagious fatal

diseases when prompt, accurate

diagnosis can mitigate risks to the

public health. Examples of the diseases

that meet these requirements are HIV/

AIDS and tuberculosis. The ASR’s used

in tests that diagnose such conditions

pose unique risks because of the

substantial clinical and public health

impact of the information generated by

these tests. The agency has concluded,

therefore, that class III controls are

appropriate.

The agency does not believe that the

application of these controls will

hamper the development of accurate

tests to respond to new conditions. FDA

has in place procedures to expedite

review of products when a device offers

a potential for clinically meaningful

benefit as compared to the existing

alternatives or when the new medical

device promises to provide a significant

advance over currently available

modalities. FDA also has issued

procedures for obtaining a humanitarian

device exemption (HDE) to encourage

the discovery and use of devices

intended to benefit patients in the

treatment or diagnosis of diseases or

conditions that affect or are manifested

in fewer than 4,000 individuals in the

United States. Therefore the agency

does not expect that this regulation will

impair the ability of clinical laboratories

to develop useful tests.

L. General Purpose Reagent in 21 CFR

864.4010

(Comment 34)

Several comments agreed with the

proposed amendment of the definition

of general purpose reagents, stating that

it clarifies the distinction between

general purpose reagents and ASR’s.

FDA agrees with these comments.

(Comment 35)

One comment claimed that ASR’s are

analogous to general purpose reagents

because both are building blocks

utilized in the development of home

brews and are sold to clinical

laboratories with no analytical or

performance claims. The comment

believed, therefore, that all ASR’s

should be class I devices, exempt from

premarket notification and CGMP’s,

except for record-keeping and complaint

files. The comment suggested that a first

logical step would be to require

registration and listing for ASR’s before

deciding what other regulatory

requirements are needed.

FDA disagrees with this comment and

notes that registration and listing are

required for ASR’s that are sold to

clinical laboratories under this

regulation. FDA believes that ASR’s are

distinguishable from general purpose

reagents because they are more complex

and have an implied intended use as the

active ingredient for in-house developed

tests. FDA has concluded, therefore, that

ASR’s merit a more stringent level of

regulation than that currently applied to

general purpose reagents.

M. Labeling

(Comment 36)

One comment stated that the ASR

supplier should only be responsible for

statements made on the ASR labeling

because the ASR manufacturers have no

control over a clinical laboratory’s

acceptance criteria for reagents. Another

comment stated that the proposed label

only goes to the identity and purity of

the ASR and does not provide any

directions for use, which would be

desirable if the goal is to provide some

regulation of in-house assays.

The agency agrees that the ASR

supplier can only be responsible for

statements made in the ASR labeling.

FDA disagrees that the ASR labeling

should include additional information.

FDA believes the labeling required by

the final rule communicates data that

are appropriate and useful to

laboratories creating in-house tests and

also will establish regulatory

consistency for all manufacturers of

ASR’s who seek to market their

products to laboratories. Directions for

use are not included in these labels

because the laboratory producing the

test, not the manufacturer of the

ingredients, is accountable for the use of

the ingredient. As mentioned earlier, the

focus of the rule is to provide regulation

of the ASR’s, not to oversee the

development of in-house testing.

(Comment 37)

One comment stated that promotional

materials need to be regulated

consistently with approved labeling, so

that the purchaser can assess differences

in product characteristics between

different suppliers.

FDA agrees with this comment and

requires promotional materials to be

consistent with appropriate labeling. In

addition, under section 502(q) of the act

(21 U.S.C. 352(q)), a restricted device is

misbranded if its advertising is false and

misleading in any particular. § 809.10(e)

delineates which product characteristics

ASR labeling must address.

(Comment 38)

One comment proposed that products

that are intended for use in diagnostic

assays should be labeled with that

intended use but that all reagents

should be freely available for basic

research.
62254 Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations

FDA agrees with this comment.

Products labeled ‘‘analyte specific

reagent’’ or ‘‘for in vitro diagnostic use’’

would not be precluded from use by

research laboratories for research

purposes. (See comment 32 of section

III.J. of this document.)

(Comment 39)

One comment from a manufacturer

doing business in the European

community suggested labeling ASR’s

‘‘for research use’’ and defining that use,

as do the Europeans, to include any

reagent product not intended for a

specific, well-defined diagnostic

application. The comment claimed that

products labeled ‘‘for in vitro diagnostic

use’’ are required to include instructions

for use in Europe while the proposed

ASR regulation does not allow

instructions for use. The comment

claimed that the conflicting labeling

regulations would restrict the ability of

small manufacturers to compete in the

global market and suggested that FDA

not require the products be labeled ‘‘for

in vitro diagnostic use.’’ Another

comment suggested that FDA should

provide a ‘‘safe harbor’’ for ASR

suppliers of the research community,

and allow such ASR suppliers to label

the products ‘‘not intended for use in

diagnostic tests.’’

FDA is interested in working with

international groups to harmonize

labeling whenever such changes are

practical and possible. FDA has

modified § 809.10(e)(9) to require the

label to read ‘‘analyte specific reagent’’

and has amended the definition of ASR

to clarify that ASR’s are intended for use

in a diagnostic application. FDA

believes these changes will address the

potential problems raised by the

comments.

N. Section 809.10(e)

(Comment 40)

One comment recommended that

§ 809.10(e) be clarified to indicate that

labeling of ASR’s may also include

information concerning expiration date,

chemical/molecular composition,

nucleic acid sequence, binding affinity,

cross-reactivities, and interference with

substances of known clinical

significance.

FDA agrees with this comment and

has modified § 809.10(e) accordingly.

O. Section 809.10(e)(9)

(Comment 41)

Two comments would add to

§ 809.10(e)(9) the following: ‘‘For

analyte specific reagent use only,’’

claiming it is consistent with the

investigational and research use labeling

for IVD’s and that it clarifies the ASR’s

regulatory status.

FDA generally agrees with these

comments and has amended the

labeling regulation to reflect that the

products are for use as analyte specific

reagents. Because these ASR’s can also

be used for research purposes, the

regulation requires the label to read

‘‘Analyte Specific Reagent,’’ rather than

‘‘For analyte specific reagent use only.’’

(Comment 42)

One comment would add to

§ 809.10(e) the following for reagents

not intended for diagnostic use: ‘‘For

laboratory research use only. CAUTION:

Not for diagnostic use. The safety and

efficacy of this product in diagnostic or

other clinical uses has not been

established.’’

FDA declines to amend the ASR

labeling regulation to include this

language. FDA believes it would be

confusing to have a requirement not

applicable to ASR’s but applicable to

‘‘research use’’ reagents in this section.

The ASR regulations are intended to

complement and be consistent with

existing regulations. Regulations

governing the labeling of research use

only products are codified at

§ 809.10(c).

P. Section 809.30(b)

(Comment 43)

One comment recommended adding

the following to § 809.30(b)(3):

‘‘educational, academic and other

research laboratories and nonclinical

laboratories,’’ stating it would minimize

confusion and avoid the need for

double-labeling of ASR’s sold for

diagnostic and research use. Another

comment suggested that FDA add

university and Government laboratories

that are performing basic research to

§ 809.30(b)(3).

FDA has amended the regulation to

include laboratories performing research

as an example of organizations that use

the reagents to make tests for purposes

other than providing diagnostic

information to patients and

practitioners. As discussed previously,

double labeling of ASR’s sold for both

diagnostic and research use will not be

necessary.

(Comment 44)

One comment recommended directing

the restrictions of § 809.30 to the users

of ASR’s rather than the sellers of ASR’s

by amending § 809.30(b) to delete, ‘‘sold

to,’’ and to add, ‘‘used in diagnostic

applications by.’’ FDA believes the concerns expressed

by this comment have been addressed.

Changes made in the final regulation

clarify that the requirements only apply

to ASR’s used in diagnostic

applications. Section 520(e) of the act

provides that FDA may restrict the sale

of a device to provide a reasonable

assurance of safety and effectiveness of

the device. FDA believes that the sale

restrictions are necessary to provide

reasonable assurance of the safe and

effective use of ASR’s; sale is restricted

to those laboratories that have the

expertise and qualifications to use

ASR’s to develop in-house tests, and to

assess the performance of the ASR’s. As

recommended by the comment, the use

of the ASR by the laboratory is also

being restricted because such use must

be associated with a disclaimer when

the ASR is incorporated by the

laboratory into a test that has not been

independently reviewed by FDA.

Q. Section 809.30(d)

(Comment 45)

One comment suggested more fully

defining ‘‘identity and purity’’ with

regard to ASR’s to include source and

method of acquisition.

FDA agrees with this comment and

modified identity and purity in § 809.30

to include source and method of

acquisition.

R. Prescription

(Comment 46)

One comment objected to any

distinction between assays that use

ARS’s and other laboratory tests with

respect to who can order or receive

results. The comment stated that: (a)

CLIA requires that laboratories follow

state laws regulating health care

providers and access to health care

testing and that FDA should not

preempt such state requirements; (b) the

implication that assays developed using

ASR’s are inherently less reliable or

harder to interpret than comparable

laboratory tests is unwarranted; and (c)

such a restriction is the regulation of the

provision of laboratory services, which

is not within FDA’s jurisdiction.

Other comments that opposed a

prescription use requirement, stated

that: (a) The ASR manufacturer does not

play a significant role in determining

the claims or uses of ASR’s; (b) there are

no clear reasons for the requirement; (c)

most States already prohibit laboratories

from reporting results directly to

patients; (d) it is unneeded because state

regulation makes all IVD tests that are

not specifically cleared or approved for

consumer self testing de facto

prescription-use devices; (e) tests that

contain ASR’s as ingredients are likely

only to be available from laboratories

qualified to perform high complexity

testing under CLIA and will not

ordinarily be available for consumer self

testing; and (f) professionals other than

physicians should also be allowed to

request tests, e.g., genetic counselors
Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations 62255

accredited by the appropriate

professional society.

One comment supported the idea that

the use of tests containing ASR’s should

require a physician’s order because the

performance characteristics of such tests

are not as well documented as OTC tests

that have been reviewed by FDA.

In the proposed rule, FDA solicited

comment on whether tests developed by

the laboratories using ASR’s should be

made available only on order of a

physician. FDA has reviewed the

comments and has decided that tests

developed by laboratories using ASR’s

should be available only on the order of

a physician or other persons authorized

by applicable state law to order such

tests. FDA disagrees with comments that

have suggested that results from inhouse assays developed using ASR’s are

no different from other IVD test results

and that OTC access to the use of ASR’s

in these settings does not raise issues of

their safety and effectiveness.

Traditionally, IVD test results are

evaluated in the context of a patient’s

history, physical examination and other

sources of diagnostic information. In

many cases, those tests are approved or

cleared by FDA and their performance

criteria have been established. Despite

that review, and as several comments

indicate, a professional intermediary is

ordinarily necessary to assure that the

test is ordered appropriately and results

are interpreted effectively. By contrast,

results of IVD tests using ASR’s may be

particularly difficult for lay persons to

interpret correctly without the guidance

of a physician because the performance

characteristics of the individual tests

often have not been cleared or approved

by FDA.

State laws vary concerning access to

in-house developed testing but FDA has

found none that establish an affirmative

right for consumers to access such

testing without the order of a health care

professional. Therefore, although FDA’s

regulations would preempt different or

additional State laws as they might

apply to in-house developed testing,

there appear to be no conflicts between

the final rule and current state

requirements. If particular situations

subsequently arise that raise questions

of preemption, FDA notes that states

may request an advisory opinion from

FDA or apply for exemptions from the

Federal regulations under section 510(k)

of the act.

Nor does FDA agree that this

restriction is an unauthorized intrusion

into the provision of laboratory services.

FDA’s focus is on safe and effective use

of ASR’s and FDA’s determination that

use should only be on the order of a

qualified health professional is

consistent with its authority to regulate

medical devices. FDA believes that

meaningful interpretation of results

based on use of ASR’s requires the

expertise of a health care practitioner

licensed by the State to provide a

reasonable assurance of the safe and

effective use of these devices. FDA is

concerned that OTC access to results

based on the use of ASR’s would require

FDA to establish more stringent

regulatory controls in order to protect

the public health. However, rather than

restricting the ordering of tests using

ASR’s to physicians only, FDA is

broadening that category to include all

health care practitioners licensed by the

State to order such tests.

IV. Access to Special Controls

The two NCCLS documents entitled

‘‘Specifications for Immunological

Testing for Infectious Disease: Approved

Guideline’’ NCCLS Document I/LA18–

A, December 1994 and ‘‘Assessment of

the Clinical Accuracy of Laboratory

Tests Using Receiver Operating

Characteristic (ROC) Plots: Tentative

Guideline’’ and NCCLS Document

KGP10–T, December 1993, may be

obtained by writing the National

Committee for Clinical Laboratory

Standards (NCCLS) at 940 West Valley

Rd., suite 1400, Wayne, PA 19087 or

calling NCCLS at 610–688–0100 or

faxing your request to NCCLS at 610–

688–0700.

To receive the document entitled

‘‘Review Criteria for Assessment of In

Vitro Diagnostic Devices for Direct

Detection of Infectious Microorganisms

spp,’’ FDA, July 6, 1993, and its

Attachment 1, February 28, 1994, via fax

machine, call the CDRH Facts-OnDemand system at 800–899–0381 or

301–827–0111 from a touch-tone

telephone. At the first voice prompt

press 1 to access Division of Small

Manufacturers Assistance (DSMA)

Facts, at second voice prompt press 2,

and then enter the document No. 862

followed by the pound sign (#). Then

follow the remaining voice prompts to

complete your request.

To receive the document from the

Center for Biologics Evaluation and

Research, FDA, entitled ‘‘Points to

Consider in the Manufacture and

Clinical Evaluation of In Vitro Tests to

Detect Antibodies to the Human

Immunodeficiency Virus, Type I 1989’’

(54 FR 48943, November 28, 1989) via

fax machine, call the CDRH Facts-OnDemand system at 800–899–0381 or

301–827–0111 from a touch-tone

telephone. At the first voice prompt

press 1 to access DSMA Facts, at second

voice prompt press 2, and then enter the

document number 662 followed by the

pound sign (#). Then follow the

remaining voice prompts to complete

your request.

The Center for Devices and

Radiological Health (CDRH), FDA,

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 Web. The CDRH

home page is updated on a regular basis

and includes: The ‘‘Draft Review

Criteria for Nucleic Acid AmplificationBased In Vitro Diagnostic Devices for

Direct Detection of Infectious

Microorganisms,’’ FDA, July 6, 1993,

document; 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.

The document entitled ‘‘Draft Criteria

for Nucleic Acid Amplification-Based In

Vitro Diagnostic Devices for Direct

Detection of Infectious

Microorganisms,’’ FDA, July 6, 1993, is

available at: ‘‘http://www.fda.gov/cdrh/

ode/odecl861.html’’.

A text-only version of the CDRH Web

site is also available from a computer or

VT–100 compatible terminal by dialing

800–22–0185 (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.

V. Analysis of Impacts

FDA has examined the impact of the

final rule under Executive Order 12866,

the Unfunded Mandates Reform Act

(Pub. L. 104–4), and the Regulatory

Flexibility Act (5 U.S.C. 601–612).

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). FDA

believes that this final rule is consistent

with the regulatory philosophy and
62256 Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations

principles identified in the Executive

Order. In addition, the final rule is not

a significant regulatory action as defined

by the Executive Order.

Title II of the Unfunded Mandates

Reform Act requires that agencies

prepare a written statement and

economic analysis for any rule that may

result in an annual expenditure by

State, local, and tribal governments, in

the aggregate, or by the private sector, of

$100 million (adjusted annually for

inflation). The expenditures required by

this rule will be far below this amount.

The Regulatory Flexibility Act

requires agencies to prepare a

Regulatory Flexibility Analysis for each

rule unless the agency certifies that the

rule would not have a significant

economic impact on a substantial

number of small entities. As explained

below, the agency estimates that this

final rule may impose significant costs

on some small businesses. However,

because FDA cannot adequately certify

the extent of this impact, it has prepared

a Regulatory Flexibility Analysis as part

of its economic assessment.

A. Purpose and Objective of the Rule

As described previously in this

document, FDA is taking this action to

classify/reclassify analyte specific

reagents (ASR’s) presenting a low risk to

public health into class I (general

controls), and to exempt those class I

ASR’s from premarket notification. FDA

is also restricting the sale, distribution,

and use of all ASR’s. FDA is regulating

these reagents to ensure that ASR’s are

manufactured with appropriate quality

controls, are labeled appropriately, and

are used by persons with adequate

qualifications to protect the public

health and safety. The rule also

classifies a small subset of ASR’s into

class II or III. Class II ASR’s are those

used in blood banking tests that have

previously been classified as class II

devices. Class III ASR’s are those used

in tests intended for use in the diagnosis

of a contagious condition that is highly

likely to result in a fatal outcome and

where prompt, accurate diagnosis offers

the opportunity to mitigate the public

health impact of the condition, or for

those used in tests intended for use in

the diagnosis of a condition for which

FDA has recommended or required

testing in order to safeguard the blood

supply or establish the safe use of blood

and biological products.

B. Type and Number of Entities Affected

This rule will predominantly affect

manufacturers and suppliers of ASR’s

that are for sale to clinical laboratories

and, to a lesser extent, the clinical

laboratories that develop and perform

in-house tests using ASR’s. Because

ASR manufacturers and suppliers have

not previously been required to register

with the agency, FDA is uncertain of the

number of entities that will be affected

by this rule. The agency estimates that

there are approximately 300 companies,

of which most, if not all, are classified

as small entities. (The Small Business

Administration defines an entity in this

industry as small if it employs less than

500 people.) HCFA estimates that there

are approximately 57,000 certified or

accredited clinical laboratories, most of

which are small, that could potentially

be required to add the statement

delineated in the regulation to their test

results. FDA does not know how many

of these laboratories currently develop

and perform in-house testing using

ASR’s.

C. Description of Economic Impact

The economic impact of this rule on

individual manufacturers and suppliers

will vary greatly. For the majority of

firms that have other products already

regulated by FDA, the added costs will

be minimal because these firms are

already required to register and list. If

there are any firms without extensive

experience producing FDA regulated

products and without a comprehensive

quality control program that produce

many ASR’s and that also derive a high

percentage of income generated from

sale of ASR’s for clinical use, those

firms will face greater costs.

1. Impact on Manufacturers and

Suppliers

Because manufacturers of ASR’s were

not previously required to register and

list with the agency, FDA does not know

the precise number of firms and profile

of the industry. The agency believes it

probable, however, that the majority of

ASR manufacturers also produce other

medical devices already regulated by

FDA and thus, can adapt their existing

procedures and controls to these new

requirements at a significantly lower

cost than firms without such

experience.

This rule requires manufacturers and

suppliers of ASR’s for sale to clinical

laboratories to: (1) Register and list their

ASR products with the agency, (2)

conform to applicable medical device

current good manufacturing practice

requirements (21 CFR part 820), (3)

comply with MDR reporting

requirements (21 CFR part 803), (4)

relabel products in accordance with this

rule, and (5) restrict the sale of ASR’s for

clinical use to clinical laboratories that

are CLIA certified as qualified to

perform high complexity testing. The

economic impact of these requirements

on individual manufacturers will vary

with a number of factors including: (1)

Whether the firm currently produces

other FDA regulated products and,

therefore, has experience with FDA

regulations, (2) the nature and number

of ASR’s produced, (3) the size of the

firm, and (4) the adequacy of the firm’s

existing quality control procedures.

a. Registration and listing. The

majority of manufacturers and suppliers

of ASR’s will incur a small cost to

register and list their products with the

agency. For manufacturers familiar with

this requirement, the average time

estimated to comply with the

registration and listing requirement is

0.8 hour per year. For those

manufacturers that do not currently

produce any FDA regulated products,

the initial registration and listing may

require up to 2 hours of time (a

combination of management and

clerical time). If half of the estimated

300 manufacturers and suppliers have

previous FDA experience, the estimated

number of hours to comply with this

requirement in the first year will be a

maximum of 420 hours for a total

industry cost of $9,555. In recurring

years, registration and listing will

require a total of 240 hours for an

industry cost of $5,460 per year.

b. CGMP and MDR compliance. The

actual costs of instituting CGMP and

MDR procedures will vary greatly and,

among other things, depend on the

number and nature of the products

produced, the size of the firm, and the

nature of its current quality control

system. FDA believes that the majority

of firms have many of the necessary

quality control procedures in place.

However, for the smaller percentage of

firms that do not currently have CGMP

and MDR procedures in place, the cost

of compliance with these two rules can

be significant.

To comply with the CGMP regulation,

manufactures will need to write and

implement standard operating

procedures for their operation, perform

appropriate validation, train their

employees, and develop, implement,

and maintain procedures for reporting

deaths and serious injuries related to

their products. There will be additional

documentation costs on an annual,

recurring basis, and some firms may

have to hire an additional person to

perform the quality assurance function.

Firms without FDA experience and

those with limited regulatory staff may

hire an industry consultant to help them

come into compliance with this rule.

FDA believes that the majority of

firms have experience producing FDArelated products. However, for the

smaller number of firms that have little
Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations 62257

or no experience producing FDAregulated products, that have limited

quality control procedures, and that

could require the help of a consultant to

assist with CGMP compliance, the onetime costs range from $50,000 to

$200,000 depending on the number of

products produced and the size of the

firm. In addition, firms that must hire a

quality assurance manager may incur

costs of $40,000 to $50,000 per year in

additional salary and documentation

costs. Alternatively, firms that produce

other medical devices under the CGMP

regulations would incur much smaller

costs because they would expand their

current procedures to include ASR

production. FDA cannot estimate the

total economic impact of these two

requirements because the agency does

not know how many of the firms that

produce ASR’s also produce other

regulated medical devices. The agency

believes, however, that the majority of

the manufacturers affected by this rule

also produce other medical devices and/

or have many of the necessary quality

control procedures in place. These firms

will incur costs significantly lower than

the $50,000 to $200,000 estimated

above.

c. Class II and III ASR’s. A small

subset of ASR’s are classified as Class II

or III devices. In addition to the general

controls, these products will also be

subject to special controls. To market

these ASR’s, manufacturers or suppliers

must have an approved 510(k) for a

class II device or a PMA for a class III

device. Because FDA will review the

performance of these ASR’s with the test

for which it is a component, the agency

believes that these ASR’s will not be

marketed as independent components.

Manufacturers of these ASR’s are either

currently marketing them to kit

manufacturers or are themselves

manufacturing the kits or tests that

already have approved 510(k)’s or

PMA’s for marketing. Thus, no costs

were estimated for this requirement.

d. Labeling. FDA is allowing

manufacturers and suppliers up to 1

year to deplete current labeling stock

before requiring compliance with the

labeling requirements. All ASR

manufacturers or suppliers must review

their labeling, including promotional

materials, to ascertain compliance with

the new labeling requirements. The

agency believes that, except for those

ASR’s sold to in vitro diagnostic

manufacturers, almost all ASR’s will

require relabeling. The economic impact

of this requirement is the one-time cost

of redesigning and reviewing the new

labeling. The agency estimates that the

cost to redesign the label is $89.50 (1

hour to redesign the label, 3 hours of

middle management review) and the

cost to redesign promotional materials is

$115.50 (1 hour to redesign materials

and 4 hours to review). Because

manufacturers have not been required to

list their products with the agency, FDA

does not know how many ASR products

are sold to clinical laboratories. Industry

experts estimate that between 5,000 and

10,000 ASR’s are marketed. Assuming

there are 7,500 ASR products, the total

cost to redesign both labels and

promotional materials is $1.5 million

($671,250 for labels, $866,250 for

promotional materials) or $205 per

product. The impact on an individual

firm will depend on the number of

products produced.

e. Restriction of sales. This rule

restricts the sale of ASR’s for clinical

use to laboratories certified to perform

high complexity testing under CLIA.

HCFA estimates that there are

approximately 57,000 accredited and

certified laboratories in the United

States. Because of the large number of

laboratories, the agency believes this

restriction will have no economic

impact on the industry. FDA received

no comments to the proposed rule that

suggested otherwise.

2. Impact on Clinical Laboratories

Clinical laboratories that develop inhouse tests using ASR’s will be required

to inform the person ordering the tests

that these tests were not cleared or

approved by FDA. In addition, ordering

of such tests is limited to physicians

and other persons authorized by

applicable State law. FDA believes the

economic impact of these two

requirements on clinical laboratories

will be minimal. As discussed earlier in

this preamble in section III.A.4 of this

document, the disclaimer is not

inconsistent with existing CLIA

requirements. In addition, both state

laws and current industry practice limit

the access of testing to trained

professionals. Moreover, no comments

were received with regard to either of

these requirements suggesting that they

would increase the economic burden on

clinical laboratories. Since FDA has not

mandated the specific means by which

clinical laboratories must comply with

the disclosure statement requirement,

laboratories that produce computer

generated reports may choose to

reprogram to add the statement, to order

preprinted report forms, or to order a

stamp. FDA estimates a one-time cost of

about $80 per establishment. However,

because FDA does not know how many

clinical laboratories develop and use inhouse tests using ASR’s, the agency

cannot estimate the total industry

impact of this requirement.

D. Analysis of Alternatives

The agency considered a number of

alternatives in developing the proposal

and this final rule. The rejected

alternatives would have created a

greater economic burden on industry

without an appreciable increase in

public health or safety. The agency

considered: (1) Enforcing its statutory

authority and regulating all

postamendment ASR’s as class III

devices subject to the premarket

approval procedures, (2) classifying a

greater number of ASR’s as class II or III

devices, and (3) requiring premarket

notification for all class I ASR’s. These

alternatives, which were discussed in

the preambles to the proposed and final

rules, were rejected because the agency

determined that for the majority of

ASR’s (the class I products) general

controls would be sufficient to ensure

that ASR’s are of consistent quality and

have appropriate labeling. As a result,

the agency believes that the current rule

is the least burdensome alternative that

meets the agency’s public health goal.

E. Response to Comments Concerning

Small Business

The major concern of small business

with regard to the economic impact of

this rule is the cost of complying with

the CGMP regulation. One comment

suggested that the CGMP regulation

should not be applied to small

companies. Another suggested that

small companies would be at a

competitive disadvantage to large firms,

suggesting that large firms could pass

through any increase in compliance

costs, while small firms would be

unable to afford the initial costs of

developing CGMP’s.

As a rule, the nature of a firm’s

existing quality system will be the major

determinant of the cost of compliance

with the CGMP regulation. The more

comprehensive a firm’s quality system

and the more closely it resembles the

CGMP, the easier it will be for a firm to

adapt its current practice. The agency

recognizes that for some firms with

limited quality control systems and no

experience manufacturing FDA

regulated products, the cost of

developing CGMP’s can be significant.

These costs would vary directly,

although not proportionally, with the

size of the firm. Smaller firms tend to

have fewer products and, thus, need to

develop fewer procedures and controls.

They also have fewer employees to

train. Larger firms are more likely than

very small firms to currently

manufacture other medical devices

already subject to CGMP’s. Such firms

would have proportionately lower
62258 Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations

compliance costs. FDA recognizes that

some of the firms that sell only a small

percentage of their products to the

clinical laboratory market may choose

not to comply with the CGMP regulation

and sell their products only to

manufacturers of IVD tests or kits, or to

research laboratories. The agency

believes, however, that this will have no

significant effect on the supply of ASR’s

to clinical laboratories.

To reduce the burden on industry,

FDA has delayed the effective date for

required CGMP compliance to 1 year

after the date of publication of this final

rule and allowed the industry time to

deplete current stock of labeling. In

addition, the agency has taken steps

specifically to assist small businesses

with compliance through the Division of

Small Manufacturers Assistance

(DSMA). DSMA provides guidance

documents through the FDA’s World

Wide Web site (http://www.fda.gov) and

fax-on-demand system (800–899–0381

or 301–827–0111), as well as

participating in agency and industry

sponsored workshops, conferences, and

meetings to inform and assist businesses

with compliance issues. In particular

‘‘The Medical Device Quality Systems

Manual: A Small Entity Compliance

Guide,’’ available on the web site,

provides examples of procedures and

forms that can be adopted and modified

by manufacturers to reduce their cost of

compliance.

F. Summary

Because the firms that would be

affected by this regulation are not

currently required to register or list their

ASR products, FDA cannot make a

precise estimate of the total cost of this

rule. The greatest cost, however, would

be to facilities that are not currently

subject to any CGMP’s. FDA does not

know how many firms would fall into

this category, but even if all of the

affected facilities needed to implement

such requirements for the first time, the

cost of the rule would be far below the

$100 million threshold that determines

an economically significant regulation

under Executive Order 12866 or the

Unfunded Mandate Reform Act. For

some individual firms, the economic

impact of this rule will be significant,

but because the agency lacks an accurate

profile of the industry, it can not

determine if a substantial number of

firms will be significantly affected.

VI. Environmental Impact

FDA has determined under 21 CFR

25.34(b) that this action is of the 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.

VII. The Paperwork Reduction Act of

1995

A. Comments on the Paperwork

Reduction Act Statement

One comment stated that the estimate

in the proposed rule of additional

recordkeeping requirements was not

accurate because the estimate did not

account for the burden resulting from

registration, listing, medical device

reporting or application of the CGMP’s.

The comment also stated that FDA

should not establish a certification

program to demonstrate compliance

with proposed restrictions.

FDA agrees that the estimate did not

contain the burden for registration,

listing, medical device reporting, or

application of CGMP’s. The registration,

listing, medical device reporting

collections of information have already

been approved by OMB (OMB control

number 0910—0059). On October 7,

1996, FDA published the CGMP final

rule (61 FR 52602) and provided a 60-

day comment period to submit written

comments to FDA on the information

collection provisions of the rule as

required under the Paperwork

Reduction Act of 1995. A notice

soliciting comments for an additional 30

days on these provisions is under

development. These burdens were not

included in the chart because any

CGMP, medical device reporting,

registration and listing requirements

have already been estimated separately.

Neither the proposed nor the final

rule contain a certification requirement.

Questions concerning certification are

addressed in section III.F. of this

document.

B. Information Collection Provisions in

the Final Rule

This final rule contains information

collection provisions that are subject to

review by OMB under the Paperwork

Reduction Act of 1995 (44 U.S. 3501–

3520). OMB did not approve FDA’s

information collection submitted to

OMB with the proposed rule. The title,

description and respondent description

of the information collection

requirements are shown below with an

estimate of the annual reporting burden.

Included in the estimate is the time for

reviewing instructions, gathering and

maintaining the data needed, and

completing and reviewing the collection

of information.

Title: Labeling Requirements for

Analyte Specific Reagents—Labeling for

Laboratories.

Description: The final rule amends the

labeling requirements for certain in vitro

diagnostic products to require that

manufacturers of analyte specific

reagents provide certain information

concerning the reagents to laboratories

that will use the reagents to develop

tests for clinical use. The final

regulation will also require that

advertising and promotional material for

analyte specific reagents include

information about the identity and

purity of the reagents and not make any

claims about analytic or clinical

performance. The purpose of the

regulation is to assure that laboratories

developing tests using these reagents

have sufficient information about their

identity and purity.

Description of Respondents:

Businesses and other for profit

organizations.

TABLE 1.—ESTIMATED ANNUAL REPORTING BURDEN

21 CFR Section No. of

Respondents

Annual

Frequency per

Response

Total Annual

Responses

Hours per

Response Total Hours

809.10(e) 300 1 300 25 7,500

809.30(d) 300 1 300 25 7,500

Total 50 15,000

The proposed rule provided a 30-day

comment period. As discussed

previously, the revised burden hour

estimates in the final rule are based

partially on comments received. FDA

has submitted the information

collection provisions of the final rule to

OMB for review. Prior to the effective

date of this final rule, FDA will publish

a notice in the Federal Register of

OMB’s decision to approve, modify, or

disapprove the information collection
Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations 62259

provisions. An agency may not conduct

or sponsor, and a person is not required

to respond to, a collection of

information unless it displays a

currently valid OMB control number.

List of Subjects

21 CFR Part 809

Labeling, Medical devices.

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 parts 809

and 864 are amended as follows:

PART 809—IN VITRO DIAGNOSTIC

PRODUCTS FOR HUMAN USE

1. The authority citation for 21 CFR

part 809 continues to read as follows:

Authority: 21 U.S.C. 331, 351, 352, 355,

357, 360b, 360c, 360d, 360h, 360i, 360j, 371,

372, 374, 381.

2. Section 809.10 is amended in

paragraph (a) by adding at the end of the

first sentence ‘‘or as provided in

paragraph (e) of this section’’ and by

adding new paragraph (e) to read as

follows:

§ 809.10 Labeling for in vitro diagnostic

products.

* * * * *

(e)(1) The labeling for analyte specific

reagents (e.g., monoclonal antibodies,

deoxyribonucleic acid (DNA) probes,

viral antigens, ligands) shall bear the

following information:

(i) The proprietary name and

established name (common or usual

name), if any, of the reagent;

(ii) A declaration of the established

name (common or usual name), if any;

(iii) The quantity, proportion, or

concentration of the reagent ingredient;

and for a reagent derived from biological

material, the source and where

applicable, a measure of its activity. The

quantity, proportion, concentration, or

activity shall be stated in the system

generally used and recognized by the

intended user, e.g., metric, international

units, etc.;

(iv) A statement of the purity and

quality of the reagent, including a

quantitative declaration of any

impurities present and method of

analysis or characterization. The

requirement for this information may be

met by a statement of conformity with

a generally recognized and generally

available standard that contains the

same information, e.g., those established

by the American Chemical Society, U.S.

Pharmacopeia, National Formulary, and

National Research Council. The labeling

may also include information

concerning chemical/molecular

composition, nucleic acid sequence,

binding affinity, cross-reactivities, and

interaction with substances of known

clinical significance;

(v) A statement of warnings or

precautions for users as established in

the regulations contained in 16 CFR part

1500 and any other warnings

appropriate to the hazard presented by

the product;

(vi) The date of manufacture and

appropriate storage instructions

adequate to protect the stability of the

product. When applicable, these

instructions shall include such

information as conditions of

temperature, light, humidity, date of

expiration, and other pertinent factors.

The basis for such instructions shall be

determined by reliable, meaningful, and

specific test methods, such as those

described in § 211.166 of this chapter;

(vii) A declaration of the net quantity

of contents, expressed in terms of

weight or volume, numerical count, or

any combination of these or other terms

that accurately reflect the contents of

the package. The use of metric

designations is encouraged, wherever

appropriate;

(viii) The name and place of business

of manufacturer, packer, or distributor;

(ix) A lot or control number,

identified as such, from which it is

possible to determine the complete

manufacturing history of the product;

(x) For class I exempt ASR’s, the

statement: ‘‘Analyte Specific Reagent.

Analytical and performance

characteristics are not established’’; and

(xi) For class II and III ASR’s, the

statement: ‘‘Analyte Specific Reagent.

Except as a component of the approved/

cleared test (Name of approved/cleared

test), analytical and performance

characteristics of this ASR are not

established.’’

(2) In the case of immediate

containers too small or otherwise unable

to accommodate a label with sufficient

space to bear all such information, and

which are packaged within an outer

container from which they are removed

for use, the information required by

paragraphs (e)(1) through (e)(6) of this

section may appear in the outer

container labeling only.

3. New § 809.30 is added to subpart C

to read as follows:

§ 809.30 Restrictions on the sale,

distribution and use of analyte specific

reagents.

(a) Analyte specific reagents (ASR’s)

(§ 864.4020 of this chapter) are

restricted devices under section 520(e)

of the Federal Food, Drugs, and

Cosmetic Act (the act) subject to the

restrictions set forth in this section.

(b) ASR’s may only be sold to:

(1) In vitro diagnostic manufacturers;

(2) Clinical laboratories regulated

under the Clinical Laboratory

Improvement Amendments of 1988

(CLIA), as qualified to perform high

complexity testing under 42 CFR part

493 or clinical laboratories regulated

under VHA Directive 1106 (available

from Department of Veterans Affairs,

Veterans Health Administration,

Washington, DC 20420); and

(3) Organizations that use the reagents

to make tests for purposes other than

providing diagnostic information to

patients and practitioners, e.g., forensic,

academic, research, and other

nonclinical laboratories.

(c) ASR’s must be labeled in

accordance with § 809.10(e).

(d) Advertising and promotional

materials for ASR’s:

(1) Shall include the identity and

purity (including source and method of

acquisition) of the analyte specific

reagent and the identity of the analyte;

(2) Shall include the statement for

class I exempt ASR’s: ‘‘Analyte Specific

Reagent. Analytical and performance

characteristics are not established’’;

(3) Shall include the statement for

class II or III ASR’s: ‘‘Analyte Specific

Reagent. Except as a component of the

approved/cleared test (name of

approved/cleared test), analytical and

performance characteristics are not

established’’; and

(4) Shall not make any statement

regarding analytical or clinical

performance.

(e) The laboratory that develops an inhouse test using the ASR shall inform

the ordering person of the test result by

appending to the test report the

statement: ‘‘This test was developed and

its performance characteristics

determined by (Laboratory Name). It has

not been cleared or approved by the

U.S. Food and Drug Administration.’’

This statement would not be applicable

or required when test results are

generated using the test that was cleared

or approved in conjunction with review

of the class II or III ASR.

(f) Ordering in-house tests that are

developed using analyte specific

reagents is limited under section 520(e)

of the act to physicians and other

persons authorized by applicable State

law to order such tests.

(g) The restrictions in paragraphs (c)

through (f) of this section do not apply

when reagents that otherwise meet the

analyte specific reagent definition are

sold to:
62260 Federal Register / Vol. 62, No. 225 / Friday, November 21, 1997 / Rules and Regulations

(1) In vitro diagnostic manufacturers;

or

(2) Organizations that use the reagents

to make tests for purposes other than

providing diagnostic information to

patients and practitioners, e.g., forensic,

academic, research, and other

nonclinical laboratories.

PART 864—HEMATOLOGY AND

PATHOLOGY DEVICES

4. The authority citation for 21 CFR

part 864 continues to read as follows:

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

360j, 371.

5. Section 864.4010 is amended by

revising paragraph (a) to read as follows:

§ 864.4010 General purpose reagent.

(a) A general purpose reagent is a

chemical reagent that has general

laboratory application, that is used to

collect, prepare, and examine specimens

from the human body for diagnostic

purposes, and that is not labeled or

otherwise intended for a specific

diagnostic application. It may be either

an individual substance, or multiple

substances reformulated, which, when

combined with or used in conjunction

with an appropriate analyte specific

reagent (ASR) and other general purpose

reagents, is part of a diagnostic test

procedure or system constituting a

finished in vitro diagnostic (IVD) test.

General purpose reagents are

appropriate for combining with one or

more than one ASR in producing such

systems and include labware or

disposable constituents of tests; but they

do not include laboratory machinery,

automated or powered systems. General

purpose reagents include cytological

preservatives, decalcifying reagents,

fixative and adhesives, tissue processing

reagents, isotonic solutions and pH

buffers. Reagents used in tests for more

than one individual chemical substance

or ligand are general purpose reagents

(e.g., Thermus aquaticus (TAQ)

polymerase, substrates for enzyme

immunoassay (EIA)).

* * * * *

6. New § 864.4020 is added to subpart

E to read as follows:

§ 864.4020 Analyte specific reagents.

(a) Identification. Analyte specific

reagents (ASR’s) are antibodies, both

polyclonal and monoclonal, specific

receptor proteins, ligands, nucleic acid

sequences, and similar reagents which,

through specific binding or chemical

reaction with substances in a specimen,

are intended for use in a diagnostic

application for identification and

quantification of an individual chemical

substance or ligand in biological

specimens. ASR’s that otherwise fall

within this definition are not within the

scope of subpart E of this part when

they are sold to:

(1) In vitro diagnostic manufacturers;

or

(2) Organizations that use the reagents

to make tests for purposes other than

providing diagnostic information to

patients and practitioners, e.g., forensic,

academic, research, and other

nonclinical laboratories.

(b) Classification. (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.

(2) Class II (special controls/guidance

documents), when the analyte is used in

blood banking tests that have been

classified as class II devices (e.g., certain

cytomegalovirus serological and

treponema pallidum nontreponemal test

reagents). Guidance Documents:

1. ‘‘Specifications for Immunological

Testing for Infectious Disease; Approved

Guideline,’’ NCCLS Document I/LA18–A,

December 1994.

2. ‘‘Assessment of the Clinical Accuracy of

Laboratory Tests Using Receiver Operating

Characteristic (ROC) Plots; Tentative

Guideline,’’ NCCLS Document KGP10–T,

December 1993.

3. ‘‘Review Criteria for Assessment of In

Vitro Diagnostic Devices for Direct Detection

of Mycobacterium spp,’’ FDA, July 6, 1993,

and its ‘‘Attachment 1,’’ February 28, 1994.

4. ‘‘Draft Review Criteria for Nucleic Acid

Amplification-Based In Vitro Diagnostic

Devices for Direct Detection of Infectious

Microorganisms,’’ FDA, July 6, 1993.

5. The Center for Biologics Evaluation and

Research, FDA, ‘‘Points to Consider in the

Manufacture and Clinical Evaluation of In

Vitro Tests to Detect Antibodies to the

Human Immunodeficiency Virus, Type I’’ (54

FR 48943, November 28, 1989).

(3) Class III (premarket approval),

when:

(i) The analyte is intended as a

component in a test intended for use in

the diagnosis of a contagious condition

that is highly likely to result in a fatal

outcome and prompt, accurate diagnosis

offers the opportunity to mitigate the

public health impact of the condition

(e.g., human immunodeficiency virus

(HIV/AIDS)or tuberculosis (TB)); or

(ii) The analyte is intended as a

component in a test intended for use in

donor screening for conditions for

which FDA has recommended or

required testing in order to safeguard

the blood supply or establish the safe

use of blood and blood products (e.g.,

tests for hepatitis or tests for identifying

blood groups).

(c) Date of 510(k), or date of PMA or

notice of completion of a product

development protocol is required. (1)

Preamendments ASR’s; No effective

date has been established for the

requirement for premarket approval for

the device described in paragraph (b)(3)

of this section. See § 864.3.

(2) For postamendments ASR’s;

November 23, 1998.

(d) Restrictions. Restrictions on the

sale, distribution and use of ASR’s are

set forth in § 809.30 of this chapter.

Dated: November 13, 1997.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 97–30334 Filed 11–20–97; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF TRANSPORTATION

Federal Highway Administration

23 CFR Part 657

RIN 2125–AE20

Truck Size and Weight; Office of

Management and Budget Control

Number and Expiration Date

AGENCY: Federal Highway

Administration (FHWA), DOT.

ACTION: Final rule; technical

amendment.

SUMMARY: This document adopts a

technical amendment to the regulations

at 23 CFR part 657 to provide the Office

of Management and Budget (OMB)

control number for the Federal Highway

Administration’s (FHWA) collection of

information from the States about their

size and weight enforcement programs

and explains the significance of

referencing that number in 23 CFR part

657.

EFFECTIVE DATE: November 21, 1997.

FOR FURTHER INFORMATION CONTACT: Mr.

Tom Klimek, Office of Motor Carrier

Information Analysis, (202) 366–2212,

or Mr. Charles Medalen, Office of the

Chief Counsel, (202) 366–1354, Federal

Highway Administration, 400 Seventh

Street, SW., Washington, D.C. 20590.

Office hours are from 7:45 a.m. to 4:15

p.m., e.s.t., Monday through Friday,

except Federal holidays.

SUPPLEMENTARY INFORMATION: Federal

law requires each State to certify to the

Secretary of Transportation before

January 1 of each year that it is

enforcing: (1) Federal law regarding (i)

vehicle weight on the Interstate System

and (ii) vehicle size on the former

Federal-aid primary, secondary and

urban systems; and (2) State size and

weight laws on the former Federal-aid

primary, secondary and urban systems

[23 U.S.C. 141(a)].