[Federal Register: November 21, 1997 (Volume 62, Number 225)]
[Rules and Regulations]
[Page 62243-62260]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr21no97-5]
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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
[[Page 62244]]
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
[[Page 62245]]
Clinical Laboratory Standards (NCCLS) documents: (1) ``Specifications
for Immunological Testing for Infectious Disease; Approved Guideline''
(December 1994, NCCLS Document I/LA18-A) and (2) ``Assessment of the
Clinical Accuracy of Laboratory Tests Using Receiver Operating
Characteristic (ROC) Plots; Tentative Guideline'' (December 1993, NCCLS
Document KGP10-T) and the following FDA guidance documents: (1)
``Review Criteria for Assessment of In Vitro Diagnostic Devices for
Direct Detection of Mycobacterium spp.'' (July 6, 1993) and its
``Attachment 1'' (February 28, 1994); (2)`` Draft Review Criteria for
Nucleic Acid Amplification-Based In Vitro Diagnostic Devices for Direct
Detection of Infectious Microorganisms'' (June 14, 1993); and (3) the
Center for Biological Evaluation and Research's ``Points to Consider in
the Manufacture and Clinical Evaluation of In Vitro Tests to Detect
Antibodies to the Human Immunodeficiency Virus, Type I'' (54 FR 48943,
November 28, 1989). FDA believes these special controls are sufficient
to ensure safe and effective use of these ASR's because these ASR's
have previously been evaluated in tests classified as class II and
cleared by FDA.
Persons interested in obtaining the documents previously referenced
should refer to section IV in this document on ``Access to Special
Controls.''
In addition to the small subset of ASR's discussed above that have
been identified as class III, FDA also has identified another small
subset of ASR's for which class III premarket approval is necessary to
protect the public health. These class III ASR's are those whose use
poses unique risks because of the substantial clinical and public
health impact of the information generated by using these devices. This
subset of ASR's are those incorporated in tests intended to diagnose
those contagious diseases that are highly likely to be fatal and where
accurate diagnosis offers an opportunity to mitigate the public health
impact of the condition or those ASR's incorporated in class III tests
intended to establish the safety of blood and blood products, including
genetic tests intended to ensure the safety of the blood supply.
Examples of class III ASR's include ASR's used in tests to diagnose
human immunodeficiency virus/acquired immune deficiency syndrome (HIV/
AIDS) or tuberculosis.
Under 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
[[Page 62246]]
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
[[Page 62247]]
classification was established for this group of ASR's because a
majority of ASR's could be used as ingredients in a genetic test, even
if they were not sold for that use.
Other comments supported different treatment for ASR's used in
genetic tests:
(a) One comment suggested that it was premature to regulate ASR's
composed of human genetic products as class I until the molecular basis
of human disease is better understood. Another comment suggested that
ASR's should be regulated as class III medical devices if the practice
of making in-house assays of genetic tests directly available to
consumers becomes widespread or problematic.
(b) Two comments recommended that ASR's used in genetic screening
tests for predictive purposes in apparently healthy persons should be
regulated more strictly than class I, for example, by requiring
premarket notification.
(c) One comment proposed that ASR's whose only labeled indications
are in the area of genetic predisposition or in prognostic situations
with long latency periods should be regulated as class II or III
devices.
(d) Two comments proposed regulating ASR's used in genetic testing
as class II devices. One comment proposed special controls for these
ASR's and no exemption from notification. The second comment would
allow the sale of ASR's to laboratories without regard to certification
by CLIA.
(e) Because the clinical validity of ASR's may be difficult to
establish, their sensitivity and predictive value may not be high, and
the benefits they confer are not proven, one comment recommended that
ASR's used in genetic screening tests for predictive purposes in
apparently healthy persons should be available on an investigational
basis only. Another comment said they should be available on an
investigative basis until clinical validity is proven, and then they
should be classified as class III devices. Two comments recommended
that they should be regulated as class III devices.
In general, FDA agrees with those comments that support regulating
ASR's used in genetic tests as class I exempt. (See the discussion in
section II.E. of this document.) The regulations were issued to apply
to ASR's as a category of device, and most ASR's can be used in a
variety of in-house developed tests. At this time, FDA does not believe
there is a scientific basis to distinguish between tests based on the
use of DNA and tests based on the use of other proteins or substances,
or between tests based on the use of DNA and tests based on the use of
other molecular diagnostic technologies. However, FDA recognizes that
there are special issues related to genetic testing or predictive
genetic testing and that these issues may affect the degree of
regulatory control needed to establish the safety and effectiveness of
these tests or the ASR's used in their development. As stated
previously, FDA intends to review its decision with respect to
regulatory control of genetic testing after it has had an opportunity
to evaluate final recommendations from NIH's Task Force on Genetics
Testing and other interested parties.
FDA believes that this final regulation will assure the quality of
material being used to develop in-house genetics tests. When used as
part of in-house developed tests, the ASR regulations restrict use of
commercially marketed ASR's to tests that are ordered by an authorized
practitioner and to those clinical laboratories regulated under CLIA as
qualified to perform high complexity testing. Except when test results
are generated using the test that was cleared or approved in
conjunction with review of the class II or III ASR, FDA is also
requiring that a disclaimer be appended to the test report stating that
the clinical laboratory determined and developed the test performance
characteristics and that the test that incorporated the ASR has not
been cleared or approved by FDA. FDA believes these restrictions
address many of the concerns raised by those comments supporting more
stringent regulation of ASR's used in genetic testing. The issuance of
these regulations does not preclude FDA from reevaluating in the future
whether additional controls may be needed for genetics testing or for
ASR's used in such tests. FDA will reevaluate whether additional
controls may be needed to provide an appropriate level of consumer
protection if further developments in this area result in significant
uses of ASR's in genetic assays or other IVD tests offered 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
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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