[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]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
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.
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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
population.
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
reagents.
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
risks.
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
follows:
1. The biological or chemical suppliers would have to register with
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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
classification.
(59 FR 37378).
FDA believes that these criteria apply to class I analyte specific
reagents and that, therefore, they may be exempted from premarket
notification.
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
devices.
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
issues.
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
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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
required.
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
purity.
Description of Respondents: Businesses and other for profit
organizations.
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Estimated Annual Reporting Burden
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21 CFR Section No. of Respondents Annual Frequency per Response Total Annual Responses Hours Per Response Total Hours
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809.10(e) 100 1 100 40 4,000
809.30(d) 100 1 100 20 2,000
Total 6,000
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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:
PART 809--IN VITRO DIAGNOSTIC PRODUCTS FOR HUMAN USE
1. The authority citation for 21 CFR part 809 continues to read as
follows:
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
Council.
(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
distributor.
(8) A lot or control number, identified as such, from which it is
possible to determine the complete manufacturing history of the
product.
(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
reagents:
(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
performance.
PART 864--HEMATOLOGY AND PATHOLOGY DEVICES
4. The authority citation for 21 CFR part 864 continues to read as
follows:
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,
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 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
laboratory
[[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]
BILLING CODE 4160-01-F