[Federal Register Volume 62, Number 225 (Friday, November 21, 1997)]
[Rules and Regulations]
[Pages 62243-62260]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-30334]


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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.

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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

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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 in-house 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

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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 Sec. 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 Sec. 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 
Sec. 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 in-
house 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

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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 
Sec. 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 Sec. 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 Sec. 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 Sec. 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 
Sec. 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 Sec. 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

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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 over-the-
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

[[Page 62248]]

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 well-being 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

[[Page 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 in-house 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 in-house 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 in-house 
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

[[Page 62250]]

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 in-house 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

[[Page 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 Sec. 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 Sec. 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 in-house 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

[[Page 62252]]

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 in-house 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

[[Page 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. 
Sec. 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.

[[Page 62254]]

    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 Sec. 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 Sec. 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 Sec. 809.10(e) 
accordingly.

O. Section 809.10(e)(9)

(Comment 41)
    Two comments would add to Sec. 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 Sec. 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 Sec. 809.10(c).

P. Section 809.30(b)

(Comment 43)
    One comment recommended adding the following to Sec. 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 Sec. 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 Sec. 809.30 
to the users of ASR's rather than the sellers of ASR's by amending 
Sec. 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 
Sec. 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

[[Page 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 in-house 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-On-Demand 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-On-Demand 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 Amplification-Based 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

[[Page 62256]]

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 
FDA-related products. However, for the smaller number of firms that 
have little

[[Page 62257]]

or no experience producing FDA-regulated products, that have limited 
quality control procedures, and that could require the help of a 
consultant to assist with CGMP compliance, the one-time 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 in-house 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 in-house 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

[[Page 62258]]

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                                  
----------------------------------------------------------------------------------------------------------------
                                                      Annual                                                    
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours 
                                    Respondents      Response        Responses       Response                   
----------------------------------------------------------------------------------------------------------------
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

[[Page 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:

Sec. 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 Sec. 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 Sec. 809.30 is added to subpart C to read as follows:

Sec. 809.30  Restrictions on the sale, distribution and use of analyte 
specific reagents.

    (a) Analyte specific reagents (ASR's) (Sec. 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 Sec. 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 in-house 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:

[[Page 62260]]

    (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:

Sec. 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 Sec. 864.4020 is added to subpart E to read as follows:

Sec. 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 Sec. 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 Sec. 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