[Federal Register Volume 61, Number 51 (Thursday, March 14, 1996)]
[Proposed Rules]
[Pages 10483-10489]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-6160]


[[Page 10484]]

21 CFR Parts 809 and 864

[Docket No. 96N-0082]

Medical Devices; Classification/Reclassification; Restricted 
Devices; Analyte Specific Reagents

AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.


SUMMARY: The Food and Drug Administration (FDA) is proposing to 
classify/reclassify analyte specific reagents (ASR) presenting a low 
risk to the public health into class I (general controls), and to 
exempt these class I analyte specific reagents from the premarket 
notification (510(k)) requirements. FDA is also proposing to designate 
class I analyte specific reagents as restricted devices under the 
Federal Food, Drug, and Cosmetic Act (the act), and to establish 
restrictions on their sale, distribution and labeling. Finally, FDA is 
proposing that ASR's presenting a high risk be classified into or 
retained in class III (premarket approval). The scope of products 
covered by this proposal includes both pre-1976 devices which have not 
been previously classified, as well as post-1976 devices which are 
statutorily classified into class III. The intention of this proposal 
is to regulate these pre- and post-1976 devices in a consistent 
fashion. Therefore, FDA is proposing classification or reclassification 
of these products, as applicable.

DATES: Written comments on the proposed rule by June 12, 1996.
    Written comments on the information collection requirements should 
be submitted by April 15, 1996.

ADDRESSES: Written comments on the proposed rule to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857.
    Submit written comments on the information collection requirements 
to the Office of Information and Regulatory Affairs, OMB, New Executive 
Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: 
Desk Officer for FDA.
FOR FURTHER INFORMATION CONTACT: Steven Gutman, Center for Devices and 
Radiological Health (HFZ-440), Food and Drug Administration, 2098 
Gaither Rd., Rockville, MD 20850, 301-594-3084.

SUPPLEMENTARY INFORMATION: The act (21 U.S.C. 201 et seq.) as amended 
by the Medical Device Amendments of 1976 (Pub. L. 94-295) (the 
amendments) and the Safe Medical Devices Act of 1990 (Pub. L. 101-
629)(SMDA) 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 provide 
reasonable assurance of their safety and effectiveness. The three 
categories of devices are as follows: Class I, general controls; class 
II, special controls; class III, premarket approval.
    Devices that were in commercial distribution before May 28, 1976 
(the date of enactment of the amendments) are classified under 21 
U.S.C. 360c 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. The agency 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).

I. Background

    There has been a growing trend in recent years for more 
sophisticated clinical laboratories to develop and prepare their own 
tests that are intended to diagnose various medical conditions, using 
ingredients that they frequently purchase from biological or chemical 
suppliers. The ingredients and other materials used in developing these 
tests may be divided into two groups. The first group is referred to as 
general purpose reagents, which include the laboratory apparatus, 
collection systems, and chemicals used broadly in a wide variety of 
tests. The second group is composed of chemicals or antibodies that may 
be thought of as the ``active ingredients'' of a test and which are 
useful only in testing for one specific disease or condition. It is 
this group of active ingredients that FDA is proposing to identify as 
ASR's. These in-house developed tests (sometimes referred to as ``home 
brew'' tests) include a wide variety used in the diagnosis of 
infectious diseases, cancer, genetic, and various other conditions. FDA 
currently regulates the safety and effectiveness of diagnostic tests 
that are traditionally manufactured and commercially marketed as 
finished products. However, in-house developed tests have not been 
actively regulated by the Agency and the ingredients used in them 
generally are not produced under FDA assured manufacturing quality 
control. Other general controls also have not been applied routinely to 
these products. FDA is not proposing a comprehensive regulatory scheme 
over the final tests produced by these laboratories and is focusing 
instead on the ``active ingredients'' (ASR's) provided to the 
laboratories. However, at a future date, the agency may reevaluate 
whether additional controls over the in-house tests developed by such 
laboratories may be needed to provide an appropriate level of consumer 
protection. Such controls may be especially relevant as testing for the 
presence of genes associated with cancer or dementing diseases becomes 
more widely available. Additional controls might include a broad array 
of approaches, ranging from full premarket review by FDA to use of 
third parties to evaluate analytical or clinical performance of the 
tests. The laboratories producing tests from ASR's and offering the 
tests as laboratory services are currently regulated by the Health Care 
Financing Administration (HCFA) under the Clinical Laboratory 
Improvement Amendments of 1988 (CLIA-88) for compliance with general 
laboratory standards regarding personnel, proficiency testing, quality 
control, and quality assurance. However, these HCFA regulations do not 
include the same product controls provided by FDA. As a result, neither 
patients nor practitioners have assurance that all ingredients in the 
laboratory developed tests are of high quality and capable of producing 
consistent results.
    FDA is concerned that the present situation with respect to in-
house developed tests, in which these ingredients are essentially 
unregulated and therefore of unpredictable quality, may create a risk 
to the public health. FDA also is concerned that continuing 
uncertainties about the regulatory status of commercially marketed 
ASR's may create an unpredictable business climate for manufacturers 
and suppliers. On the other hand, the agency recognizes the clinical 
importance of in-house developed testing as a mechanism for

[[Page 10485]]
providing novel, highly specialized tests in a relatively short time, 
sometimes for diseases that affect a relatively small proportion of the 
    FDA's primary goals in this rulemaking proceeding are to assure 
that ASR's are high quality reagents and that performance claims are 
restricted to those made by the final test developer. In addition, for 
those select ASR's whose use present a particularly high risk to public 
health, FDA seeks to ensure a higher and more appropriate level of 
regulatory review.
    To seek public and expert input on these issues, FDA held a meeting 
of its Immunology Devices Panel (the Panel) on January 22, 1996. In the 
notice announcing that meeting (61 FR 74-75, January 2, 1996), FDA set 
forth its preliminary thinking regarding a regulatory framework for 
ASR's. That framework included placing the majority of ASR's into class 
I and exempting them from premarket notification requirements; 
maintaining other general controls, including registration, listing, 
and compliance with current good manufacturing practice (CGMP) and 
medical device reporting (MDR) requirements; and restrictions on the 
sale, distribution or use of these devices. Also, under that framework, 
a small number of ASR's presenting a high risk to public health would 
be placed in class III.
    At the public session of the Panel meeting, a variety of health 
professional and industry organizations presented their views. These 
groups included: American Association for Clinical Chemistry, American 
Clinical Laboratories Association, Association for Molecular Pathology, 
College of American Pathologists, Centocor, Inc., Health Industry 
Manufacturers Association, IBT Reference Laboratory, Joint Council of 
Immunohistochemical Manufacturers, and Specialty Laboratories Inc. In 
general, these groups supported the broad outline of the FDA approach 
(Ref. 1).

II. The Immunology Devices Panel Recommendation

    At the January 22, 1996 meeting, the Panel made the following 
recommendations regarding the classification of analyte specific 
    1. Identification: The Panel recommended that these devices be 
identified as follows: ``Analyte specific reagents are antibodies (both 
monoclonal and polyclonal), specific receptor proteins, nonhuman 
nucleic acids and fragments of nonhuman nucleic acids and similar 
biological reagents which, through specific chemical binding or 
reaction, are intended for diagnostic identification or quantification 
of specific analytes in a biological specimen.'' (Ref. 1.)
    2. Recommended classifications: The Panel recommended that most of 
these devices be classified into Class I (general controls); that these 
devices be exempted from the premarket notification (510(k)) 
requirements; and that these devices be subject to the good 
manufacturing practices regulation as well as to other general 
controls, including restrictions on their distribution and labeling. 
The panel also recommended that certain ASR's should be classified into 
class II or class III, or as regulated by the Center for Biologics 
Evaluation and Research, because their use presents particularly high 
    3. Summary of reasons for recommendation: The Panel recommended 
that most analyte specific reagents be classified into class I because 
they believed that general controls are sufficient to provide 
reasonable assurance of their safety and effectiveness.The Panel did 
not believe that premarket review was an appropriate or necessary 
mechanism for assuring the safe and effective use of these reagents.
    The Panel's classification recommendation was based on the 
applicability of the general controls usually associated with class I 
products (e.g., registration, listing, CGMP, and MDR) as well as the 
inclusion of restrictions on distribution, use, and labeling. The Panel 
believed that compliance with CGMP's by ASR suppliers was essential to 
ensure the quality and purity of ASR's purchased by clinical 
laboratories. The Panel also believed that restricting distribution of 
these ASR's to laboratories certified as high complexity laboratories 
under CLIA would ensure that these devices would be properly used by 
qualified health professionals. The Panel also believed that it would 
be appropriate to require that high complexity laboratories, when 
reporting results from in-house developed tests using ASR's, include a 
disclaimer stating that the in-house developed tests had not been 
reviewed by FDA. The Panel believed that this disclaimer would provide 
clinicians with additional information to be used in deciding how much 
weight to place on the test results being reported. Finally, the Panel 
recommended that manufacturers of ASR's be prohibited from labeling 
their product with analytical or clinical performance claims. The Panel 
believed that it would be inappropriate for manufacturers to make 
specific claims because these products are intended to be used as 
ingredients in a variety of ways by high complexity laboratories. Under 
these circumstances, performance would be established by the laboratory 
using the ASR's.
    While the Panel believed that class I designation and exemption 
from 510(k) was appropriate for most analyte specific reagents, the 
Panel was of the opinion that there were some instances in which 
general controls would not be sufficient. They suggested that:
    those analyte specific reagents intended to diagnose 
communicable diseases or where the Agency has established a 
recommendation for use of the test in safeguarding the blood supply 
or establishing the safe use of blood and blood products and/or 
tests to predict genetic disease or predisposition to disease in 
healthy or apparently healthy individuals are more properly 
classified into Class II or III and subject to premarket controls, 
510(k) or PMA as applicable to such classifications. (Ref. 1.)
The Panel believed that ASR's used in these settings present risks to 
the public health that require heightened regulatory control.
    4. Summary of data on which panel recommendation is based: The 
Immunology Devices Panel based its recommendation on the Panel members 
personal knowledge of, and clinical experience with, the devices and 
presentations by Panel members and interested parties (Ref. 1).
    5. Risks to health: The primary risk to health presented by these 
products is that they may be manufactured with variable quality, or be 
inappropriately labeled, or be used by persons without adequate 
qualifications. There is also concern that clinicians ordering the 
tests made from ASR's may be unaware that the clinical performance 
characteristics of these tests have not been independently reviewed by 
FDA. The Panel also 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.
    The Panel discussed FDA's approach to regulating ASR's without 
regard to whether the particular ASR's are pre-1976 or post-1976 
devices. FDA believes that the Panel's thinking and conclusions may be 
reasonably applied to the classification of pre-1976 ASR's as well as 
to the reclassification of post-1976 ASR's (which, by statute, are 
already in class III).

III. FDA's Proposed Rule

    FDA is proposing that most active ingredients used in preparing in-
house developed tests be classified as class I and regulated as 
    1. The biological or chemical suppliers would have to register with

[[Page 10486]]
FDA and provide the agency with a list of the ASR's they are supplying 
to laboratories for use in developing tests. These suppliers would be 
required to follow good manufacturing practices, as applicable, in 
accordance with 21 CFR part 820. The suppliers would also have to 
report to FDA, under 21 CFR part 803, adverse events that may have been 
due to their ingredients.
    2. These class I devices would be exempt from the premarket 
notification requirements of section 510(k) of the act. Most recently, 
in the Federal Register of July 21, 1994 (59 FR 37378), FDA set out its 
criteria for exempting devices from premarket notification. In part, 
this document states that a device may be exempted if the following 
factors apply:
    (a) Characteristics of the device necessary for its safe and 
effective performance are well established; (b) anticipated changes 
in the device that could affect safety and effectiveness will 
either: (1) be readily detectable by users by visual examination or 
other means such as routine testing, before causing harm, e.g., 
testing of a clinical laboratory reagent with positive and negative 
controls; or (2) not materially increase the risk of injury, 
incorrect diagnosis, or ineffective treatment; and any changes in 
the device would not be likely to result in a change in the device's 
(59 FR 37378).
FDA believes that these criteria apply to class I analyte specific 
reagents and that, therefore, they may be exempted from premarket 
    3. Section 520(e) of the act (21 U.S.C. 360j(e)) provides that FDA 
may by regulation require that a device be restricted in its sale, 
distribution, or use only upon the written or oral authorization of a 
practitioner licensed by law to administer or use such device, or upon 
such other conditions as FDA may prescribe in the regulation, if, 
because of its potentiality for harmful effect or the collateral 
measures necessary to its use, FDA determines that there cannot 
otherwise be reasonable assurance of its safety and effectiveness. FDA 
is proposing that use of these active ingredients to produce in-house 
developed tests be restricted to those clinical laboratories certified 
under CLIA-88 as ``high-complexity laboratories.'' These laboratories 
have the expertise and qualifications required to use these active 
ingredients in making in-house tests, and to assess the performance of 
the ASR's. FDA believes that these qualifications are necessary to 
provide reasonable assurance of the safe and effective use of these 
    4. Under the proposal, the labeling for the active ingredients to 
be used in these in-house tests would be restricted to describing the 
identity and purity of the material being sold in addition to most of 
the standard information already required for general purpose reagents 
(e.g., net weight; storage instructions). However, under this proposal 
no specific analytical or clinical performance claims could be made in 
the labeling or in promotional material. This is because the laboratory 
producing the test, not the manufacturer of the ingredients, is 
accountable for use of the ingredient and its performance as part of a 
test. Also, under section 520(e) of the act, the advertising and 
promotional material for ASR's would be restricted in a manner 
consistent with the labeling. As discussed in section IV of this 
document, FDA invites comments on the Panel's recommendation regarding 
labeling in test reports from clinical laboratories to health 
professionals. Finally, FDA is proposing to revise the definition of 
general purpose reagents to complement and be consistent with the 
definition being proposed for ASR's.
    In addition to the proposed classification of most ASR's in class 
I, FDA is proposing that certain active ingredients used in in-house 
developed tests be classified either in class III subject to premarket 
approval because of the serious health risks associated with their use 
or in the class of the test in which the ASR is being used, or 
regulated under other appropriate mechanisms. These include active 
ingredients used in tests intended to diagnose potentially fatal 
contagious conditions (e.g., human immunodeficiency virus (HIV) or 
tuberculosis) or intended to safeguard the blood supply. The proposed 
restrictions on the distribution, use, and labeling of ASR's in class I 
would also apply to any ASR placed in class II or class III. As 
described in section IV of this document, the agency is seeking public 
input on the Panel's recommendation that this group of reserved ASR's 
should also include those active ingredients which are intended for use 
in human genetic testing.
    If this proposal is made final, marketing of post-1976 ASR's in 
class III would need to cease following publication of the final rule 
until premarket approval applications (PMA's) were submitted and 
approved. The number of firms and products that would be affected would 
be a function of how many ASR's are classified in class III in the 
final rule. FDA believes that, as proposed, only a very few companies 
and products would be affected. For pre-1976 devices, following 
publication of a final rule on classification, companies would be 
required to submit 510(k)'s as an interim measure. Companies would then 
have a minimum of 30 months to develop safety and effectiveness data 
necessary to support a PMA.

IV. Unresolved Questions; Request for Comments

    A number of important issues were raised during the Panel 
discussion as specified below. FDA is inviting comments on all of these 
    1. The Panel expressed concern that the controls recommended by FDA 
for analyte specific reagents used in in-house developed tests were not 
sufficiently stringent for the active ingredients used in human genetic 
testing, and suggested that these ingredients be regulated as class II 
or class III devices. FDA believes that this recommendation by the 
panel may be too broad. For example, FDA is not certain that making a 
distinction among tests that directly identify genetic material (i.e., 
deoxyribonucleic acid (DNA), which the panel recommended for class II 
or III) as opposed to transcribed genetic material (i.e., m-RNA) or 
gene products (i.e.,proteins and post-translationally modified 
proteins, which the panel recommended for class I) provides a 
meaningful basis for differing regulatory treatment of ASR's that are 
used to develop these tests. FDA is therefore soliciting comments on 
the full range of options available to regulate ASR's intended for use 
in human genetic testing: From regulating these ASR's as class I exempt 
products to regulating them as class III devices subject to premarket 
approval. Intermediate options include regulating a subset of these 
ASR's as class III devices. For example, FDA could regulate as class 
III devices only those ASR's used 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 long (5 years or longer). FDA 
is soliciting comments on the degree of regulatory control needed for 
these tests and reasonable bases for distinction , if any, among the 
ASR's used for human genetic testing.
    2. The panel recommended that the definition of ASR's not include 
human nucleic acids. (See ``Panel Recommendation'' above.) FDA believes 
that this would be too narrow and has excluded the word ``nonhuman'' 
from its proposed definition. FDA believes that if ASR's for human 
genetic sequencing are to be excluded in a final rule from class I 
exempt status, it would

[[Page 10487]]
be preferable to do so by describing the basis for such exclusion in 
the rule and explicitly reserving those ASR's for class II or III, as 
has been proposed for ASR's used in tests intended to safeguard the 
blood supply. FDA also believes that the use of the phrase ``specific 
analytes'' in the Panel's recommended definition of ASR's is circular 
and has replaced it in the definition with: ``and quantification of an 
individual chemical substance or ligand in biological substances.'' FDA 
invites comments on these changes.
    3. FDA is also soliciting comments on the suitability of the term 
``analyte-specific reagent'' to describe the active ingredients in in-
house developed tests.
    4. The Panel recommended that a disclaimer be appended to the test 
report informing the ordering practitioner of the test results. The 
disclaimer would inform the practitioner that the test was developed, 
and its performance characteristics defined, by the laboratory without 
FDA review. The agency is seeking comment on whether such a disclaimer 
should be required and, if so, how it should be worded. One possible 
statement would be: ``This test was developed and its performance 
characteristics determined by [Laboratory Name]. It has not been 
reviewed by the U.S. Food and Drug Administration.'' In addition, FDA 
solicits comments on whether the tests developed by the laboratories 
using ASR's should be made available only on the order of a physician, 
or, alternatively, whether ASR's intended for use in tests made 
directly available to consumers should be regulated in class II or III.

V. Comments

    Interested persons may, on or before June 12, 1996, submit to the 
Dockets Management Branch (address above) written comments regarding 
this proposal. Two copies of any comments are to be submitted, except 
that individuals may submit one copy. Comments are to be identified 
with the docket number found in brackets in the heading of this 
document. Received comments may be seen in the office above between 9 
a.m. and 4 p.m., Monday through Friday.

VI. Reference

    The following reference has been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Transcript of the Immunology Devices Panel of the Medical 
Devices Advisory Committee meeting, January 22, 1996.

VII. Environmental Impact

    The agency has determined under 21 CFR 25.24(e)(2) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 

VIII. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the proposed 
rule is not a significant regulatory action as defined by the Executive 
Order and so is not subject to review under the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because this proposed rule would not require 
premarket review of the vast majority of products, the agency certifies 
that the proposed rule will not have a significant economic impact on a 
substantial number of small entities. Therefore, under the Regulatory 
Flexibility Act, no further analysis is required.

IX. Paperwork Reduction Act of 1995

    This proposed rule contains information collections which are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995. The title, description, and 
respondent description of the information collection 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.
    With respect to the following collection of information, FDA 
invites comments on: (1) Whether the proposed collection of information 
is necessary for proper performance of FDA's functions, including 
whether the information will have practical utility; (2) the accuracy 
of FDA's estimate of the burden of the proposed collection of 
information, including validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate and other forms of 
information technology.
    Title: Labeling Requirements for Analyte Specific Reagents-Labeling 
for Laboratories
    Description: The proposed rule would amend 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 develop tests using 
the reagents. The proposed regulation would also require that 
advertising and promotional material for analyte specific reagents 
include information about the identity and purity of the reagent 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 
    Description of Respondents: Businesses and other for profit 

                                                            Estimated Annual Reporting Burden                                                           
   21 CFR Section         No. of Respondents      Annual Frequency per Response  Total Annual Responses      Hours Per Response          Total Hours    
809.10(e)             100                         1                              100                     40                          4,000              
809.30(d)             100                         1                              100                     20                          2,000              
Total                                                                                                                                6,000              

[[Page 10488]]

    There are no capital costs or operating and maintenance costs 
associated with these information collections.
    As required by section 3507(d) of the Paperwork Reduction Act of 
1995, FDA has submitted the collections of information contained in the 
proposed rule to OMB for review. Other organizations and individuals 
desiring to submit comments regarding the burden estimate or any aspect 
of these information collection requirements, including suggestions for 
reducing the burden, should direct them to the Office of Information 
and Regulatory Affairs, OMB, New Executive Office Bldg., 725 17th St. 
NW., rm. 10235, Washington, DC 20503, Attn: Desk Officer for FDA. 
Written comments on the information collection requirements should be 
submitted by April 15, 1996.

 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, it is 
proposed that 21 CFR parts 809 and 864 be amended as follows:


    1. The authority citation for 21 CFR part 809 continues to read as 

    Authority: Secs. 301, 501, 502, 505, 507, 512, 513, 514, 518, 
519, 520, 701, 702, 704, 801 of the Federal Food, Drug, and Cosmetic 
Act (21 U.S.C. 331, 352, 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) The labeling for analyte specific reagents (e.g., monoclonal 
antibodies, deoxyribonucleic acid (DNA) probes, viral antigens) shall 
bear the following information:
    (1) The proprietary name and established name (common or usual 
name), if any, of the reagent.
    (2) A declaration of the established name (common or usual name), 
if any, and 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.
    (3) A statement of the purity and quality of the reagent, including 
a quantitative declaration of any impurities present. The requirement 
for this information may be met by a statement of conformity with a 
generally recognized and generally available standard which contains 
the same information, e.g., those established by the American Chemical 
Society, U.S. Pharmacopeia, National Formulary, National Research 
    (4) 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.
    (5) 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, 
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.
    (6) 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 which accurately reflect the contents of the package. 
The use of metric designations is encouraged, wherever appropriate.
    (7) Name and place of business of manufacturer, packer, or 
    (8) A lot or control number, identified as such, from which it is 
possible to determine the complete manufacturing history of the 
    (9) The statement ``Analytical and performance characteristics are 
not established.''
    (10) 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 read as follows:

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

    (a) Analyte specific reagents (Sec. 864.4020 of this chapter) are 
restricted devices under section 520(e) of the act subject to the 
restrictions set forth in this section.
    (b) Analyte specific reagents may only be sold to:
    (1) In vitro diagnostic manufacturers;
    (2) Clinical laboratories certified as high complexity laboratories 
under 42 CFR part 493; or
    (3) Organizations that use the reagents to make tests for purposes 
other than providing diagnostic information to patients and 
practitioners, e.g., forensic or underwriting laboratories.
    (c) Analyte specific reagents must be labeled in accordance with 
Sec. 809.10(e).
    (d) Advertising and promotional materials for analyte specific 
    (1) Shall include the identity and purity of the analyte specific 
reagent and the identity of the analyte;
    (2) Shall include the statement ``Analytical and performance 
characteristics are not established''; and
    (3) Shall not make any statement regarding analytical or clinical 


    4. The authority citation for 21 CFR part 864 continues to read as 

    Authority: Secs. 501, 510, 513, 515, 520, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 351, 360, 360c, 360e, 360j, 

    5. Section 864.4010 is amended by revising paragraph (a) to read as 

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 histopathology, 
cytology, and hematology, 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 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 
more than one analyte specific reagent in producing such systems and 
include labware or disposable constituents of tests but do not include 

[[Page 10489]]
machinery, automated or powered systems. General purpose reagents 
include cytological preservatives, decalcifying reagents, fixatives 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., 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 are antibodies, both 
polyclonal and monoclonal, specific receptor proteins, nucleic acid 
sequences, and similar biological reagents which, through chemical 
binding or reaction with substances in a specimen, are intended for 
identification and quantification of an individual chemical substance 
or ligand in biological specimens.
    (b) Classification.
    (1) Class I (General Controls), except as described in paragraph 
(b)(2) of this section. These devices are exempt from the premarket 
notification requirements in part 807, subpart E of this chapter.
    (2) These devices are in Class III (Premarket Approval), when:
    (i) The analyte is used to develop a test intended to diagnose a 
contagious condition and the condition 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) or tuberculosis); or
    (ii) The analyte is used to develop a test intended to diagnose 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, 
syphilis, or blood grouping antisera).
    (3) ASR's that meet the criteria in paragraph (b)(2) of this 
section but are used to develop tests that have been classified by FDA 
into class I or class II are classified into the same class as the test 
for which they are being used.
    (c) Date PMA or notice of completion of a PDP 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)(2) of this section. See Sec. 864.3.
    (2) For postamendments ASR's; (effective date of the final rule).

    Dated: March 8, 1996.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 96-6160 Filed 3-11-96; 4:01 pm]