[Federal Register Volume 62, Number 225 (Friday, November 21, 1997)]
[Rules and Regulations]
[Pages 62243-62260]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-30334]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 809 and 864
[Docket No. 96N-0082]
RIN 0910-ZA03
Medical Devices; Classification/Reclassification; Restricted
Devices; Analyte Specific Reagents
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
to classify/reclassify analyte specific reagents (ASR's) presenting a
low risk to public health into class I (general controls), and to
exempt these class I devices from the premarket notification (510(k))
requirements. FDA is classifying/reclassifying ASR's used in certain
blood banking tests as class II (special controls) because general
controls are insufficient to provide a reasonable assurance of safety
and effectiveness. Finally, ASR's presenting a high risk are being
classified or retained in class III (premarket approval). FDA is also
designating all ASR's as restricted devices under the Federal Food,
Drug, and Cosmetic Act (the act), and establishing restrictions on
their sale, distribution and use. The scope of products covered by this
final rule includes both pre-1976 devices, which have not been
previously classified, as well as post-1976 devices, which are
statutorily classified into class III. The intent of this final rule is
to regulate these pre- and post-1976 devices in a consistent fashion.
This rulemaking does not affect requirements for reagents that are
subject to licensure under the Public Health Service Act (the PHS Act).
This rulemaking also does not affect reagents sold to nonclinical
settings, including those reagents sold as components to manufacturers
of cleared or approved in vitro diagnostic tests.
DATES: This rule is effective November 23, 1998.
FOR FURTHER INFORMATION CONTACT: Steven I. Gutman, Center for Devices
and Radiological Health (HFZ-440), Food and Drug Administration, 2098
Gaither Rd., Rockville, MD 20850, 301-594-3084.
SUPPLEMENTARY INFORMATION:
I. Background
The the act (21 U.S.C. 201 et seq.), as amended by the Medical
Device
[[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
[[Page 62249]]
used in developing a test intended for use in the: (a) Diagnosis of a
contagious condition that is likely to result in a fatal outcome and
where prompt accurate diagnosis offers the opportunity to mitigate the
public health impact of the condition; (b) screening of a condition for
which FDA has established a recommendation or requirement for the use
of the test in safeguarding the blood supply or establishing the safe
use of blood and blood products (e.g., hepatitis or tests for
identifying blood groups); or (c) screening for blood banking when
screening test has been classified as a class II device. Currently, FDA
believes that ASR's used to test for evidence and monitoring for levels
of HIV/AIDS and tuberculosis (TB) are examples that would fall within
the class III exception, and reagents used in the diagnosis of diseases
caused by cytomegaloviruses and treponema pallidum nontreponemal test
reagents which aid in the diagnosis of syphilis fall within the class
II exception.
Most blood banking tests fall into class III and some into class
II. Class II blood banking tests fall into two categories. One category
consists of blood banking tests required by FDA to screen for diseases
with a low potential for transmission, e.g., syphilis. The second
category consists of certain blood banking tests used electively by
blood banks to screen for diseases that are likely to be transmitted to
subsets of blood unit recipients known to be at greater risk of
infection, e.g., cytomegalovirus. Because these blood banking tests
have previously been classified into class II, FDA has determined that
special controls are sufficient and that the submission of a premarket
approval application (PMA) associated with a class III device is not
necessary for the ASR used in the test.
(Comment 9)
One comment suggested that only those ASR's with the lowest risk
factor for generating false results of little consequence should be
classified as class I, and that the others should be classified as
class II or III. The comment reasoned that the reliable, reproducible
performance of a diagnostic test is dependent upon the entire
integration of the test system. The comment also stated that while
laboratories qualified to do high complexity testing have experience in
utilizing and evaluating test systems developed by manufacturers, these
laboratories do not have expertise in developing in vitro diagnostic
tests. The comment noted that CLIA does not require the validation of
diagnostic tests systems by rigorously controlled clinical trials to
establish expected values and performance characteristics. Such trials
are not required by CLIA but could be required by FDA if these tests
were placed in class II or III.
FDA has considered this and related comments and appreciates the
concerns raised about the development of in-house tests and the current
marketing of test services based on tests that have not been reviewed
independently for safety and effectiveness. FDA believes that clinical
laboratories that develop such tests are acting as manufacturers of
medical devices and are subject to FDA jurisdiction under the act.
However, FDA recognizes that the use of in-house developed tests has
contributed to enhanced standards of medical care in many circumstances
and that significant regulatory changes in this area could have
negative effects on the public health. For these reasons, FDA declines
to accept the suggestion that all in-house developed tests be
classified as class II or III medical devices. FDA views this final
rule as a reasonable regulatory step at this time and an important
contribution to assuring that the primary ingredients of most in-house
developed tests are manufactured properly, used by trained
professionals, and labeled accurately.
The focus of this rule is the classification and regulation of
ASR's that move in commerce, not tests developed in-house by clinical
laboratories or ASR's created in-house and used exclusively by that
laboratory for testing services. The regulation restricts the sale of
ASR's to a particular type of laboratory and FDA believes this
restriction supports the safe and effective use of these ASR's. FDA
believes that CLIA regulated laboratories qualified to perform high
complexity testing have demonstrated expertise and ability to use ASR's
in test procedures and analyses. In addition, the disclaimer being
required by this rule will provide physicians with more complete
information to better understand the basis of test development and to
evaluate the information generated by the laboratory using the ASR.
Nevertheless, FDA understands that the use of ASR's to develop in-
house tests raise questions about the safety and effectiveness of the
tests that incorporate these ASR's. FDA has determined that certain
types of testing raise public health concerns that require more
stringent regulation of the ASR's that are the main ingredients of
those tests: testing for highly contagious and fatal diseases and
testing that protects the safety of the blood supply require different
and additional review. As proposed, FDA is now classifying the ASR's
associated with such testing into class III. In addition, FDA is
classifying into class II those ASR's that are used in blood banking
tests which previously have been classified into class II. These class
II and III devices will be reviewed in association with the test that
is incorporating the ASR so that FDA can assure a level of safety and
effectiveness that is commensurate with the intended use of the ASR. In
addition, ASR's and tests using ASR's that meet the definition of a
biologic remain subject to licensure under the PHS Act.
Finally, FDA notes that the comment misunderstood the requirements
under CLIA with respect to tests in the waived category. Under CLIA,
manufacturers are required to submit studies to demonstrate that the
statutory criteria for waiver are met, and any waived test must either
be approved/cleared by FDA for home use or be simple, easy to perform,
and essentially error free. The Centers for Disease Control and
Prevention (CDC) is responsible for implementing the categorization
provision of CLIA, including waived States.
(Comment 10)
One comment expressed concern that FDA has not fully discussed
regulating moderate risk products and suggested that the level of
sophistication of diagnostic technology requires more than two
categories.
Although the final rule establishes three classes of ASR's, FDA
disagrees that most moderate risk ASR's require additional regulation.
FDA believes that the classification of most ASR's as restricted class
I devices in conjunction with existing CLIA regulations and
professional organization's standards applicable to laboratories
qualified to do high complexity testing is adequate for regulating
ASR's used in both low and moderate risk in-house assays. In addition,
FDA has identified a small subset of ASR's used in class II blood
banking tests that require special controls to provide a reasonable
assurance of safety and effectiveness and that will be regulated as
class II devices. The regulation represents an incremental regulatory
change and does not preclude future regulatory activity by FDA or other
Federal or professional groups involved in oversight of laboratory
activities from developing mechanisms to improve the quality of
laboratory practice or test production.
(Comment 11)
Several comments objected to any FDA regulation of ASR's. One of
these suggested that FDA should work with HCFA to amend HCFA's
regulation of clinical laboratories if changes in current regulation of
home brews are
[[Page 62250]]
necessary, claiming that FDA's regulation in this area would only
increase the administrative costs of medical care. Another comment
stated that: (a) There is an absence of safety or effectiveness
concerns in ASR use; (b) regulating ASR's increases the burden on FDA's
scarce resources and facilities; (c) CLIA regulation is sufficient; and
(d) the proposed rule does not target the party best suited to address
issues of analytical validity, which is the laboratory preparing the
in-house test. Another comment expressed concern that the proposed rule
encourages in-house production of ASR's. Another comment suggested
providing guidances rather than regulating by rulemaking.
FDA disagrees with these comments. FDA intends that this final
rule, developed with input from HCFA and CDC, complement existing
regulations issued under CLIA. FDA's rule establishes a basic
requirement that manufacturers of ASR's for use in clinical
laboratories comply with appropriate CGMP's. CGMP procedures and
controls are designed to ensure high quality devices. FDA believes that
high quality ASR's are likely to lower costs of developing and
maintaining test systems at individual laboratory sites and to
decrease, rather than increase, total medical costs.
FDA regards regulating ASR's using general controls and exempting
them from the premarket notification requirements as a minimal burden
and an appropriate level of regulation for devices that pose less
safety or effectiveness concerns than devices marketed as test systems
or test kits. In keeping with this approach, this rule addresses
quality and identity of the ASR's and does not address analytic
validity of the devices. FDA does not expect this regulation to
independently increase efforts by laboratories to develop ASR's in-
house. FDA believes that the in-house development of ASR's is driven by
research goals, and is not a practice that grows in response to
regulatory efforts. Finally, while it may be necessary for FDA to
develop guidances concerning ASR's in the future, FDA believes that
establishing a classification for ASR's through rulemaking is the
appropriate mechanism to ensure consistent regulation of these devices
for their manufacturers and users.
(Comment 12)
One comment suggested that the Panel's recommendation would
unfairly burden the manufacturer of the ASR and that the clinical
laboratory was the best party to ensure that the appropriate restraints
are placed on interpretation of a diagnostic test through a disclaimer
provision.
FDA agrees in part with the comment. FDA intends to minimize the
regulatory burden on ASR manufacturers by regulating most ASR's as
class I devices exempt from premarket notification. The final rule
requires that a disclaimer be appended to the test report by the
laboratory that uses the ASR. That statement will inform the ordering
practitioner that: ``This test was developed and its performance
characteristics determined by (Laboratory Name). It has not been
cleared or approved by the U.S. Food and Drug Administration.'' The
statement would not be applicable or required when test results are
generated using the test that was cleared or approved in conjunction
with review of the class II or III ASR.
(Comment 13)
One comment expressed concern about regulating the ASR ingredient,
rather than the final test product, claiming that most clinical
laboratories will not establish the clinical performance of a
diagnostic product via properly controlled and population
representative clinical trials.
FDA understands the concern raised by this comment but disagrees
that regulation of ASR's will not be useful and that regulation of all
in-house developed tests is appropriate at this time. As discussed
previously, FDA has concluded that its regulation of ASR's will
contribute to consistency and quality in their manufacture and that the
requirement that the laboratory using the ASR explain the regulatory
status of the test in which it was used will increase the information
available to physicians ordering these tests. Development of in-house
laboratory tests is a complex process in which diagnostic performance
may be assessed either through the medical practice associated with a
given laboratory or scientific literature. Although the types of trials
performed in support of these tests are likely to be variable,
laboratories will be responsible for both the quality and
interpretation of results generated from these tests.
(Comment 14)
One comment questioned whether FDA has the resources to require
CGMP compliance from all ASR manufacturers and prevent the
inappropriate use of ``research use only'' labeling.
FDA believes it does have resources to enforce the requirements
established by this regulation. The regulation requires all ASR
manufacturers to follow general controls and, as with other FDA
regulations, it is primarily the responsibility of the manufacturer to
comply with the regulations pertaining to ASR's. FDA intends to monitor
the level of compliance through inspections and, where necessary, take
enforcement actions. FDA also expects that the clinical laboratory and
physician community will join manufacturers in encouraging compliance;
laboratories purchasing these ASR's and physicians ordering tests using
these ASR's will now expect them to be produced consistently in
accordance with appropriate CGMP's.
(Comment 15)
One comment suggested regulating the ASR by the same classification
as the final assay.
FDA disagrees with this comment. A single class I ASR may be
potentially used in multiple different versions of a final assay, which
are developed and run by individual clinical laboratories. Basing the
regulation of every class I ASR on the final assay developed and run by
individual clinical laboratories, therefore, would be problematic. FDA
believes that existing mechanisms for laboratory oversight under the
mandate of CLIA are sufficient in most cases to assure proper test
control.
(Comment 16)
One comment requested information on how the proposed rule relates
to the immunohistochemical (IHC) regulation and the definition of
IHC's, the Compliance Policy Guide (CPG) for the Distribution of
Research and Investigational Use Products, and other classification
actions currently underway.
Depending on their labeling and intended use, devices for use as
IHC stains could be marketed under a variety of options. When an IHC is
developed as a kit or system for ``in vitro diagnostic use'' (with a
proposed intended use, indications for use, instructions for use, and
performance characteristics), it would be subject to review as a class
I, II, or III device according to intended use as outlined in the
proposed IHC regulation (61 FR 30197, June 14, 1996). When an IHC is
developed and marketed as an ASR (intended for ASR use only, with no
instructions for use, and no defined performance characteristics), it
would be subject to general controls and restrictions established by
this final regulation but would be exempt from premarket review. When
an IHC is developed and used only for ``research use'' or
``investigational use,'' it would be subject to appropriate labeling
only with no requirement for premarket review or compliance with the
general controls or restrictions of this ASR regulation.
In August of 1992, FDA invited comment on a draft CPG entitled
[[Page 62251]]
``Commercialization of Unapproved In Vitro Diagnostic Devices Labeled
for Research and Investigation,'' which was intended to clarify the
regulation of devices ``for research use'' or ``for investigational
use'' and to describe FDA's enforcement policy concerning research or
investigational IVD's that are being illegally commercialized for
diagnostic or prognostic purposes. Any final CPG issued on this subject
will be consistent with the ASR regulations.
(Comment 17)
One comment recommended that FDA create a task force to assist FDA
in further delineating and defining issues raised in the proposed rule.
FDA believes that the comments submitted in response to the
proposed rule provide the assistance FDA sought in delineating and
defining the issues raised in the proposed rule and believes that it is
unnecessary to institute an additional procedure at this time to
address these issues. Where products pose new or unusual risks, FDA may
seek assistance in classifying the products.
C. Adverse Event Reporting
(Comment 18)
One comment objected to the requirement that the ASR supplier be
required to report adverse events and asserted that it would add an
unnecessary step to the reporting process because ASR suppliers depend
on the clinical laboratory to inform them of the occurrence of an
adverse event.
FDA disagrees with this comment. This requirement is consistent
with the medical device reporting regulations in part 803, which
require device user facilities and manufacturers to report deaths and
serious injuries to which a device has or may have caused or
contributed, and to establish and maintain an adverse event file. Under
these regulations, the burden for reporting adverse events is shared by
both health care providers and manufacturers. If a number of events
become associated with a particular ASR, it is the manufacturer who is
likely to be in the best position to investigate the cause of the
adverse events and to take corrective action, if necessary.
D. ASR Definition in Sec. 864.4020(a)
(Comment 19)
One comment expressed concern that the proposed definition of ASR's
would adversely impact basic research, noting that it included every
polyclonal or monoclonal antibody specific to a human antigen and every
oligonucleotide primer used in polynerase chain reaction (PCR), reverse
transcription or labeled for use in detecting hybridization, including
those whose primary or entire use is in basic research.
FDA does not intend to have this regulation apply to basic research
and has amended the definition of ASR Sec. 864.4020(a) to clarify that
the regulation applies only to reagents intended for use in a
diagnostic application.
(Comment 20)
One comment would add the term ``ligand'' to the proposed ASR
definition, stating it is the ligand which binds to the categories of
materials that are proposed to be within the ASR definition. Two
comments would add ``diagnostic'' to the definition to clarify that an
ASR is only intended for diagnostic use. One comment suggested amending
the ASR definition to read ``specific binding or chemical reaction,''
noting that binding between ASR's and analytes is often through
physical means and that ASR's may also react chemically with analytes.
FDA agrees with the suggested clarifications and has modified the
definition accordingly.
(Comment 21)
One comment stated that the chemical or biological source of a
reagent should not preclude it from being identified as an ASR.
FDA agrees with this comment and believes that the definition of
ASR's supports this concept.
E. Blood Supply
(Comment 22)
Two comments supported the regulations of ASR's used in tests
intended to safeguard the blood supply as class III devices.
FDA agrees with these comments and will continue to classify ASR's
used in tests intended to safeguard the blood supply as class III
devices because of the serious health risks associated with their use
in that setting. As discussed previously, ASR's used in tests that
previously have been classified in class II, will be class II, rather
than class III. ASR's and tests using ASR's that meet the definition of
a biologic remain subject to licensure under the PHS Act.
(Comment 23)
One comment questioned whether it is consistent to apply class II
or III and other regulatory requirements to manufacturers of ASR's used
in blood banking tests and suggested it would be more appropriate to
have the regulatory focus be on the developer of the in-house assay.
Although FDA has concluded that class I is an appropriate
classification for most ASR's, FDA believes that regulation of the
blood supply requires maximum assurance of safety, and that ASR's used
in tests intended to safeguard the blood supply require a different and
more stringent level of control. Accordingly, ASR's used for tests that
are intended to assure the safety of the blood supply will be reviewed
in association with the test that is going to incorporate that ASR. The
concern of the comment is addressed, therefore, because the test will
be reviewed in order to establish that the ASR can be used safely and
effectively. FDA's Center for Biologic Evaluation and Research (CBER)
will continue to take the lead in the review of such products and
should be the point of contact for manufacturers of ASR's that are
intended to be used in tests relating to the safety of the blood
supply. These tests remain subject to licensure under the PHS Act.
(Comment 24)
One comment expressed concern that labeling test results using
ASR's as not having been reviewed by FDA would restrict the use of
valuable reagents used in immunohematology and suggested that the
regulation of blood bank/immunohematology tests be specifically
addressed by a panel of expert serologists.
FDA does not believe that the situation suggested by the comment is
likely to occur. CBER has not licensed any biologic that is used in
tests intended to safeguard the blood supply without reviewing and
approving the test that will incorporate that biologic. This policy
will not be affected by this final rule. Under this policy, an ASR
should not be incorporated into a home brew test designed to protect
the safety of the blood supply unless that test has been approved by
FDA or is being investigated under an effective investigational new
drug application. Because these ASR's would only be used in association
with tests that have already been approved, the disclaimer would not be
applicable or required when test results are generated using the test
that was cleared or approved in conjunction with review of the class II
or III ASR.
F. Certification
(Comment 25)
Several comments recommended that FDA not require ASR suppliers to
certify that sales comply with the proposed sale restrictions, claiming
that such certification would be a recordkeeping burden.
These comments appear to have misread the rule. There was no
certification requirement in the
[[Page 62252]]
proposed ASR regulation and none has been included in the final rule.
The ASR rule does not require ASR suppliers to certify that sales
comply with the proposed sale restrictions.
G. CGMP's
(Comment 26)
Several comments objected to the application of CGMP's where ASR's
are rare reagents made only once or so infrequently that CGMP's cannot
be properly applied, or where ASR's are reagents made in an academic or
research setting, or by very small companies. One comment suggested
that acceptance specifications developed by individual laboratories for
key ingredients and test performance criteria would determine an
individual laboratory's standard for acceptability for manufacturing
those ASR's.
In response to these comments, FDA notes that manufacturers are not
required to follow CGMP's for reagents made and used within academic or
research settings. For rare or infrequently made ASR's, FDA intends to
apply only those provisions of the CGMP's as are appropriate to ensure
the quality and purity of the ASR's being marketed for clinical
applications. However, the size of a company that commercially markets
ASR's will not exempt that manufacturer from compliance with
appropriate CGMP's.
H. Economics
(Comment 27)
One comment stated that carefully controlled and documented
performance of IVD tests will curb medical care costs by contributing
to more specific diagnosis and more selective patient management. This
comment suggested that FDA's regulation of ASR's is not stringent
enough and that FDA should regulate in-house developed tests the same
way FDA regulates other IVD's.
FDA believes that applying general controls to the majority of
ASR's used to develop in-house tests is, in conjunction with CLIA
certification of the laboratory, the appropriate degree of regulatory
control. As discussed previously, FDA appreciates the concerns that
have been raised about in-house developed tests that are not reviewed
independently. If future developments in laboratory technologies or
marketing of in-house developed tests indicate that additional
regulation is necessary to provide an appropriate level of consumer
protection, FDA may reevaluate whether additional controls over in-
house developed tests are warranted.
(Comment 28)
Several comments expressed concern that the proposed regulations
will increase the cost of diagnostic tests and/or decrease the
availability of those reagents that are low use/low revenue products.
The comments suggested that large companies will pass along the
increased costs to consumers and that small companies will be unable to
comply because the cost is prohibitively expensive. A comment also
questioned what the regulatory impact would be on a clinical laboratory
that both manufactures the ASR and uses the ASR in an in-house test.
FDA believes that the ASR regulations are a minimal regulatory
burden and should improve the assurance of quality for purchasers of
ASR's for use in test development without significantly increasing
costs. In response to the concern that this regulation will eliminate
the manufacture of low use ASR's, FDA notes that it has recently
published regulations for humanitarian device exemption procedures (61
FR 33232, June 26, 1996) which could be applied to low use/low revenue
products to prevent disruption of this important market. As explained
previously, ASR's developed in-house and not marketed to other
laboratories generally would not be subject to the ASR requirements
established under the final rule. However, as noted previously, ASR's
and tests incorporating ASR's that meet the definition of a biologic
that are intended to protect the blood supply will remain subject to
licensure under the PHS Act.
I. Sales Restriction to CLIA Regulated Laboratories That Perform High
Complexity Testing
(Comment 29)
One comment objected to the restriction of sales of ASR's to CLIA
laboratories that perform high complexity testing, stating that such
laboratories may lack training and/or experience in such tests. The
comment suggested that the sale of ASR's should be restricted to a
laboratory's area of testing, rather than complexity of testing.
Another comment stated that CLIA'88 does not provide assurance of
safety and efficacy of tests because it does not require assessment of
a test's clinical validity or utility. Several comments supported the
proposed restriction of sales to laboratories qualified to perform high
complexity testing under CLIA because CLIA established minimum
standards for proficiency testing, quality assurance, quality control,
and personnel.
FDA believes that restriction to a laboratory regulated under CLIA
or comparable laws regulating Veterans Affairs laboratories as
qualified to perform high complexity testing will ensure that these
devices are handled in a setting that complies with the most stringent
Federal regulatory standards for laboratory practice. FDA believes that
these laboratory practice standards are a more appropriate regulatory
distinction than areas of speciality, which may often overlap and are
difficult to define.
FDA recognizes that CLIA does not require laboratories to assess
the clinical validity of in-house developed tests. Nor do FDA's ASR
regulations address the clinical validity of these tests. The purpose
of restricting the sale of ASR's to laboratories qualified to perform
high complexity testing under CLIA is to make certain that these
devices are being handled by individuals whose training and experience
are likely to assure the safe and effective use of the ASR's
themselves. FDA currently believes that regulating the active
ingredients of in-house developed tests should provide an appropriate
level of regulation to protect the public health. However, the ASR
regulations do not preclude FDA or other Federal agencies from taking
other measures authorized by law to assure assessment of a test's
clinical validity or utility if such measures are needed. As stated
previously, at a future date, FDA may reevaluate whether additional
controls over the in-house tests are warranted to provide an
appropriate level of consumer protection.
(Comment 30)
One comment asked how ASR manufacturers can identify laboratories
qualified to perform high complexity testing and whether ASR suppliers
would be required to re-assess a laboratory's classification on an
annual basis.
The ASR regulations require ASR manufacturers to label and market
ASR's appropriately. FDA is allowing manufacturers and suppliers until
November 23, 1998 to deplete their current stock of lables before
requiring compliance with the labeling requirements. While the ASR
regulations do not require ASR suppliers to certify sales to
laboratories qualified to perform high complexity testing, such
voluntary certification programs may be one way to ensure proper
marketing of ASR's. Information concerning whether a particular
laboratory is qualified to perform high complexity testing may be
obtained by calling the State survey agency in the State where the
laboratory is located.
(Comment 31)
Two comments stated that CLIA does not certify or regulate European
clinical
[[Page 62253]]
laboratories. The comments suggested that, in foreign countries, ASR's
be sold in accordance with the laws of that country.
FDA agrees and does not expect the ASR regulations to affect the
marketing of ASR's to laboratories or suppliers in foreign countries.
J. Research
(Comment 32)
One comment asked whether ASR's could be sold to universities doing
pure research, and if so, would such ASR's require a separate research
use only (RUO) label.
ASR's can be sold to universities doing research and FDA has
amended 809.30 to clarify this point. ASR's and products labeled ``for
in vitro diagnostic use'' can be used for research purposes so an
additional label would not be necessary in those circumstances.
However, products that have not been manufactured in accordance with
CGMP's and are labeled ``for research use only'' cannot be marketed
under the ASR classification or used by laboratories to develop
clinical diagnostics.
K. Contagious Fatal Diseases
(Comment 33)
Two comments supported the regulation of ASR's used in tests
intended for use in the diagnosis of potentially fatal contagious
diseases as class III devices. Several comments objected to classifying
such ASR's as class III, stating that: (a) Stricter regulation will
impair the ability of the clinical laboratories to respond rapidly to
outbreaks of new or emerging infectious diseases, (b) the patient
population is small, (c) the proposed regulation of other ASR's
provides sufficient regulation, and (d) it will cause confusion in a
variety of situations, for instance, where the disease typically is not
fatal, but occasionally may cause fatalities, or where an ASR may be
used for multiple purposes, ranging from screening procedures to
monitoring treatment or progression of disease, or where an ASR is used
for the diagnosis of both infectious and noninfectious diseases. One
comment suggested that it would be more appropriate to require
premarket notification for these ASR's or to regulate them as class II
devices that require premarket notification and special controls,
rather than classify these ASR's as class III.
FDA does not believe that regulating this limited category of ASR's
as class III devices will confuse the industry or interfere with
laboratory development of tests. ASR's will be identified as class III
devices only when they are intended to be used either in tests that
establish or safeguard the safety of the blood supply or in tests that
diagnose contagious fatal diseases when prompt, accurate diagnosis can
mitigate risks to the public health. Examples of the diseases that meet
these requirements are HIV/AIDS and tuberculosis. The ASR's used in
tests that diagnose such conditions pose unique risks because of the
substantial clinical and public health impact of the information
generated by these tests. The agency has concluded, therefore, that
class III controls are appropriate.
The agency does not believe that the application of these controls
will hamper the development of accurate tests to respond to new
conditions. FDA has in place procedures to expedite review of products
when a device offers a potential for clinically meaningful benefit as
compared to the existing alternatives or when the new medical device
promises to provide a significant advance over currently available
modalities. FDA also has issued procedures for obtaining a humanitarian
device exemption (HDE) to encourage the discovery and use of devices
intended to benefit patients in the treatment or diagnosis of diseases
or conditions that affect or are manifested in fewer than 4,000
individuals in the United States. Therefore the agency does not expect
that this regulation will impair the ability of clinical laboratories
to develop useful tests.
L. General Purpose Reagent in 21 CFR 864.4010
(Comment 34)
Several comments agreed with the proposed amendment of the
definition of general purpose reagents, stating that it clarifies the
distinction between general purpose reagents and ASR's.
FDA agrees with these comments.
(Comment 35)
One comment claimed that ASR's are analogous to general purpose
reagents because both are building blocks utilized in the development
of home brews and are sold to clinical laboratories with no analytical
or performance claims. The comment believed, therefore, that all ASR's
should be class I devices, exempt from premarket notification and
CGMP's, except for record-keeping and complaint files. The comment
suggested that a first logical step would be to require registration
and listing for ASR's before deciding what other regulatory
requirements are needed.
FDA disagrees with this comment and notes that registration and
listing are required for ASR's that are sold to clinical laboratories
under this regulation. FDA believes that ASR's are distinguishable from
general purpose reagents because they are more complex and have an
implied intended use as the active ingredient for in-house developed
tests. FDA has concluded, therefore, that ASR's merit a more stringent
level of regulation than that currently applied to general purpose
reagents.
M. Labeling
(Comment 36)
One comment stated that the ASR supplier should only be responsible
for statements made on the ASR labeling because the ASR manufacturers
have no control over a clinical laboratory's acceptance criteria for
reagents. Another comment stated that the proposed label only goes to
the identity and purity of the ASR and does not provide any directions
for use, which would be desirable if the goal is to provide some
regulation of in-house assays.
The agency agrees that the ASR supplier can only be responsible for
statements made in the ASR labeling. FDA disagrees that the ASR
labeling should include additional information. FDA believes the
labeling required by the final rule communicates data that are
appropriate and useful to laboratories creating in-house tests and also
will establish regulatory consistency for all manufacturers of ASR's
who seek to market their products to laboratories. Directions for use
are not included in these labels because the laboratory producing the
test, not the manufacturer of the ingredients, is accountable for the
use of the ingredient. As mentioned earlier, the focus of the rule is
to provide regulation of the ASR's, not to oversee the development of
in-house testing.
(Comment 37)
One comment stated that promotional materials need to be regulated
consistently with approved labeling, so that the purchaser can assess
differences in product characteristics between different suppliers.
FDA agrees with this comment and requires promotional materials to
be consistent with appropriate labeling. In addition, under section
502(q) of the act (21 U.S.C. 352(q)), a restricted device is misbranded
if its advertising is false and misleading in any particular.
Sec. 809.10(e) delineates which product characteristics ASR labeling
must address.
(Comment 38)
One comment proposed that products that are intended for use in
diagnostic assays should be labeled with that intended use but that all
reagents should be freely available for basic research.
[[Page 62254]]
FDA agrees with this comment. Products labeled ``analyte specific
reagent'' or ``for in vitro diagnostic use'' would not be precluded
from use by research laboratories for research purposes. (See comment
32 of section III.J. of this document.)
(Comment 39)
One comment from a manufacturer doing business in the European
community suggested labeling ASR's ``for research use'' and defining
that use, as do the Europeans, to include any reagent product not
intended for a specific, well-defined diagnostic application. The
comment claimed that products labeled ``for in vitro diagnostic use''
are required to include instructions for use in Europe while the
proposed ASR regulation does not allow instructions for use. The
comment claimed that the conflicting labeling regulations would
restrict the ability of small manufacturers to compete in the global
market and suggested that FDA not require the products be labeled ``for
in vitro diagnostic use.'' Another comment suggested that FDA should
provide a ``safe harbor'' for ASR suppliers of the research community,
and allow such ASR suppliers to label the products ``not intended for
use in diagnostic tests.''
FDA is interested in working with international groups to harmonize
labeling whenever such changes are practical and possible. FDA has
modified Sec. 809.10(e)(9) to require the label to read ``analyte
specific reagent'' and has amended the definition of ASR to clarify
that ASR's are intended for use in a diagnostic application. FDA
believes these changes will address the potential problems raised by
the comments.
N. Section 809.10(e)
(Comment 40)
One comment recommended that Sec. 809.10(e) be clarified to
indicate that labeling of ASR's may also include information concerning
expiration date, chemical/molecular composition, nucleic acid sequence,
binding affinity, cross-reactivities, and interference with substances
of known clinical significance.
FDA agrees with this comment and has modified Sec. 809.10(e)
accordingly.
O. Section 809.10(e)(9)
(Comment 41)
Two comments would add to Sec. 809.10(e)(9) the following: ``For
analyte specific reagent use only,'' claiming it is consistent with the
investigational and research use labeling for IVD's and that it
clarifies the ASR's regulatory status.
FDA generally agrees with these comments and has amended the
labeling regulation to reflect that the products are for use as analyte
specific reagents. Because these ASR's can also be used for research
purposes, the regulation requires the label to read ``Analyte Specific
Reagent,'' rather than ``For analyte specific reagent use only.''
(Comment 42)
One comment would add to Sec. 809.10(e) the following for reagents
not intended for diagnostic use: ``For laboratory research use only.
CAUTION: Not for diagnostic use. The safety and efficacy of this
product in diagnostic or other clinical uses has not been
established.''
FDA declines to amend the ASR labeling regulation to include this
language. FDA believes it would be confusing to have a requirement not
applicable to ASR's but applicable to ``research use'' reagents in this
section. The ASR regulations are intended to complement and be
consistent with existing regulations. Regulations governing the
labeling of research use only products are codified at Sec. 809.10(c).
P. Section 809.30(b)
(Comment 43)
One comment recommended adding the following to Sec. 809.30(b)(3):
``educational, academic and other research laboratories and nonclinical
laboratories,'' stating it would minimize confusion and avoid the need
for double-labeling of ASR's sold for diagnostic and research use.
Another comment suggested that FDA add university and Government
laboratories that are performing basic research to Sec. 809.30(b)(3).
FDA has amended the regulation to include laboratories performing
research as an example of organizations that use the reagents to make
tests for purposes other than providing diagnostic information to
patients and practitioners. As discussed previously, double labeling of
ASR's sold for both diagnostic and research use will not be necessary.
(Comment 44)
One comment recommended directing the restrictions of Sec. 809.30
to the users of ASR's rather than the sellers of ASR's by amending
Sec. 809.30(b) to delete, ``sold to,'' and to add, ``used in diagnostic
applications by.''
FDA believes the concerns expressed by this comment have been
addressed. Changes made in the final regulation clarify that the
requirements only apply to ASR's used in diagnostic applications.
Section 520(e) of the act provides that FDA may restrict the sale of a
device to provide a reasonable assurance of safety and effectiveness of
the device. FDA believes that the sale restrictions are necessary to
provide reasonable assurance of the safe and effective use of ASR's;
sale is restricted to those laboratories that have the expertise and
qualifications to use ASR's to develop in-house tests, and to assess
the performance of the ASR's. As recommended by the comment, the use of
the ASR by the laboratory is also being restricted because such use
must be associated with a disclaimer when the ASR is incorporated by
the laboratory into a test that has not been independently reviewed by
FDA.
Q. Section 809.30(d)
(Comment 45)
One comment suggested more fully defining ``identity and purity''
with regard to ASR's to include source and method of acquisition.
FDA agrees with this comment and modified identity and purity in
Sec. 809.30 to include source and method of acquisition.
R. Prescription
(Comment 46)
One comment objected to any distinction between assays that use
ARS's and other laboratory tests with respect to who can order or
receive results. The comment stated that: (a) CLIA requires that
laboratories follow state laws regulating health care providers and
access to health care testing and that FDA should not preempt such
state requirements; (b) the implication that assays developed using
ASR's are inherently less reliable or harder to interpret than
comparable laboratory tests is unwarranted; and (c) such a restriction
is the regulation of the provision of laboratory services, which is not
within FDA's jurisdiction.
Other comments that opposed a prescription use requirement, stated
that: (a) The ASR manufacturer does not play a significant role in
determining the claims or uses of ASR's; (b) there are no clear reasons
for the requirement; (c) most States already prohibit laboratories from
reporting results directly to patients; (d) it is unneeded because
state regulation makes all IVD tests that are not specifically cleared
or approved for consumer self testing de facto prescription-use
devices; (e) tests that contain ASR's as ingredients are likely only to
be available from laboratories qualified to perform high complexity
testing under CLIA and will not ordinarily be available for consumer
self testing; and (f) professionals other than physicians should also
be allowed to request tests, e.g., genetic counselors
[[Page 62255]]
accredited by the appropriate professional society.
One comment supported the idea that the use of tests containing
ASR's should require a physician's order because the performance
characteristics of such tests are not as well documented as OTC tests
that have been reviewed by FDA.
In the proposed rule, FDA solicited comment on whether tests
developed by the laboratories using ASR's should be made available only
on order of a physician. FDA has reviewed the comments and has decided
that tests developed by laboratories using ASR's should be available
only on the order of a physician or other persons authorized by
applicable state law to order such tests. FDA disagrees with comments
that have suggested that results from in-house assays developed using
ASR's are no different from other IVD test results and that OTC access
to the use of ASR's in these settings does not raise issues of their
safety and effectiveness. Traditionally, IVD test results are evaluated
in the context of a patient's history, physical examination and other
sources of diagnostic information. In many cases, those tests are
approved or cleared by FDA and their performance criteria have been
established. Despite that review, and as several comments indicate, a
professional intermediary is ordinarily necessary to assure that the
test is ordered appropriately and results are interpreted effectively.
By contrast, results of IVD tests using ASR's may be particularly
difficult for lay persons to interpret correctly without the guidance
of a physician because the performance characteristics of the
individual tests often have not been cleared or approved by FDA.
State laws vary concerning access to in-house developed testing but
FDA has found none that establish an affirmative right for consumers to
access such testing without the order of a health care professional.
Therefore, although FDA's regulations would preempt different or
additional State laws as they might apply to in-house developed
testing, there appear to be no conflicts between the final rule and
current state requirements. If particular situations subsequently arise
that raise questions of preemption, FDA notes that states may request
an advisory opinion from FDA or apply for exemptions from the Federal
regulations under section 510(k) of the act.
Nor does FDA agree that this restriction is an unauthorized
intrusion into the provision of laboratory services. FDA's focus is on
safe and effective use of ASR's and FDA's determination that use should
only be on the order of a qualified health professional is consistent
with its authority to regulate medical devices. FDA believes that
meaningful interpretation of results based on use of ASR's requires the
expertise of a health care practitioner licensed by the State to
provide a reasonable assurance of the safe and effective use of these
devices. FDA is concerned that OTC access to results based on the use
of ASR's would require FDA to establish more stringent regulatory
controls in order to protect the public health. However, rather than
restricting the ordering of tests using ASR's to physicians only, FDA
is broadening that category to include all health care practitioners
licensed by the State to order such tests.
IV. Access to Special Controls
The two NCCLS documents entitled ``Specifications for Immunological
Testing for Infectious Disease: Approved Guideline'' NCCLS Document I/
LA18-A, December 1994 and ``Assessment of the Clinical Accuracy of
Laboratory Tests Using Receiver Operating Characteristic (ROC) Plots:
Tentative Guideline'' and NCCLS Document KGP10-T, December 1993, may be
obtained by writing the National Committee for Clinical Laboratory
Standards (NCCLS) at 940 West Valley Rd., suite 1400, Wayne, PA 19087
or calling NCCLS at 610-688-0100 or faxing your request to NCCLS at
610-688-0700.
To receive the document entitled ``Review Criteria for Assessment
of In Vitro Diagnostic Devices for Direct Detection of Infectious
Microorganisms spp,'' FDA, July 6, 1993, and its Attachment 1, February
28, 1994, via fax machine, call the CDRH Facts-On-Demand system at 800-
899-0381 or 301-827-0111 from a touch-tone telephone. At the first
voice prompt press 1 to access Division of Small Manufacturers
Assistance (DSMA) Facts, at second voice prompt press 2, and then enter
the document No. 862 followed by the pound sign (#). Then follow the
remaining voice prompts to complete your request.
To receive the document from the Center for Biologics Evaluation
and Research, FDA, entitled ``Points to Consider in the Manufacture and
Clinical Evaluation of In Vitro Tests to Detect Antibodies to the Human
Immunodeficiency Virus, Type I 1989'' (54 FR 48943, November 28, 1989)
via fax machine, call the CDRH Facts-On-Demand system at 800-899-0381
or 301-827-0111 from a touch-tone telephone. At the first voice prompt
press 1 to access DSMA Facts, at second voice prompt press 2, and then
enter the document number 662 followed by the pound sign (#). Then
follow the remaining voice prompts to complete your request.
The Center for Devices and Radiological Health (CDRH), FDA,
maintains an entry on the World Wide Web (WWW) for easy access to
information, including text, graphics, and files that may be downloaded
to a PC with access to the Web. The CDRH home page is updated on a
regular basis and includes: The ``Draft Review Criteria for Nucleic
Acid Amplification-Based In Vitro Diagnostic Devices for Direct
Detection of Infectious Microorganisms,'' FDA, July 6, 1993, document;
device safety alerts; Federal Register reprints; information on
premarket submissions (including lists of approved applications and
manufacturers' addresses); small manufacturers' assistance; and
information on video conferencing and electronic submissions,
mammography matters, and other device-oriented information. The CDRH
home page may be accessed at http://www.fda.gov/cdrh. The document
entitled ``Draft Criteria for Nucleic Acid Amplification-Based In Vitro
Diagnostic Devices for Direct Detection of Infectious Microorganisms,''
FDA, July 6, 1993, is available at: ``http://www.fda.gov/cdrh/ode/
odecl861.html''.
A text-only version of the CDRH Web site is also available from a
computer or VT-100 compatible terminal by dialing 800-22-0185 (terminal
settings are 8/1/N). Once the modem answers, press ENTER several times
and then select menu choice 1: FDA BULLETIN BOARD SERVICE. From there
follow instructions for logging in, and at the BBS TOPICS PAGE, arrow
down to the FDA home page (do not select the first CDRH entry). Then
select MEDICAL DEVICES AND RADIOLOGICAL HEALTH. From there select
CENTER FOR DEVICES AND RADIOLOGICAL HEALTH for general information, or
arrow down for specific topics.
V. Analysis of Impacts
FDA has examined the impact of the final rule under Executive Order
12866, the Unfunded Mandates Reform Act (Pub. L. 104-4), and the
Regulatory Flexibility Act (5 U.S.C. 601-612). Executive Order 12866
directs agencies to assess all costs and benefits of available
regulatory alternatives and, when regulation is necessary, to select
regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). FDA believes that this
final rule is consistent with the regulatory philosophy and
[[Page 62256]]
principles identified in the Executive Order. In addition, the final
rule is not a significant regulatory action as defined by the Executive
Order.
Title II of the Unfunded Mandates Reform Act requires that agencies
prepare a written statement and economic analysis for any rule that may
result in an annual expenditure by State, local, and tribal
governments, in the aggregate, or by the private sector, of $100
million (adjusted annually for inflation). The expenditures required by
this rule will be far below this amount.
The Regulatory Flexibility Act requires agencies to prepare a
Regulatory Flexibility Analysis for each rule unless the agency
certifies that the rule would not have a significant economic impact on
a substantial number of small entities. As explained below, the agency
estimates that this final rule may impose significant costs on some
small businesses. However, because FDA cannot adequately certify the
extent of this impact, it has prepared a Regulatory Flexibility
Analysis as part of its economic assessment.
A. Purpose and Objective of the Rule
As described previously in this document, FDA is taking this action
to classify/reclassify analyte specific reagents (ASR's) presenting a
low risk to public health into class I (general controls), and to
exempt those class I ASR's from premarket notification. FDA is also
restricting the sale, distribution, and use of all ASR's. FDA is
regulating these reagents to ensure that ASR's are manufactured with
appropriate quality controls, are labeled appropriately, and are used
by persons with adequate qualifications to protect the public health
and safety. The rule also classifies a small subset of ASR's into class
II or III. Class II ASR's are those used in blood banking tests that
have previously been classified as class II devices. Class III ASR's
are those used in tests intended for use in the diagnosis of a
contagious condition that is highly likely to result in a fatal outcome
and where prompt, accurate diagnosis offers the opportunity to mitigate
the public health impact of the condition, or for those used in tests
intended for use in the diagnosis of a condition for which FDA has
recommended or required testing in order to safeguard the blood supply
or establish the safe use of blood and biological products.
B. Type and Number of Entities Affected
This rule will predominantly affect manufacturers and suppliers of
ASR's that are for sale to clinical laboratories and, to a lesser
extent, the clinical laboratories that develop and perform in-house
tests using ASR's. Because ASR manufacturers and suppliers have not
previously been required to register with the agency, FDA is uncertain
of the number of entities that will be affected by this rule. The
agency estimates that there are approximately 300 companies, of which
most, if not all, are classified as small entities. (The Small Business
Administration defines an entity in this industry as small if it
employs less than 500 people.) HCFA estimates that there are
approximately 57,000 certified or accredited clinical laboratories,
most of which are small, that could potentially be required to add the
statement delineated in the regulation to their test results. FDA does
not know how many of these laboratories currently develop and perform
in-house testing using ASR's.
C. Description of Economic Impact
The economic impact of this rule on individual manufacturers and
suppliers will vary greatly. For the majority of firms that have other
products already regulated by FDA, the added costs will be minimal
because these firms are already required to register and list. If there
are any firms without extensive experience producing FDA regulated
products and without a comprehensive quality control program that
produce many ASR's and that also derive a high percentage of income
generated from sale of ASR's for clinical use, those firms will face
greater costs.
1. Impact on Manufacturers and Suppliers
Because manufacturers of ASR's were not previously required to
register and list with the agency, FDA does not know the precise number
of firms and profile of the industry. The agency believes it probable,
however, that the majority of ASR manufacturers also produce other
medical devices already regulated by FDA and thus, can adapt their
existing procedures and controls to these new requirements at a
significantly lower cost than firms without such experience.
This rule requires manufacturers and suppliers of ASR's for sale to
clinical laboratories to: (1) Register and list their ASR products with
the agency, (2) conform to applicable medical device current good
manufacturing practice requirements (21 CFR part 820), (3) comply with
MDR reporting requirements (21 CFR part 803), (4) relabel products in
accordance with this rule, and (5) restrict the sale of ASR's for
clinical use to clinical laboratories that are CLIA certified as
qualified to perform high complexity testing. The economic impact of
these requirements on individual manufacturers will vary with a number
of factors including: (1) Whether the firm currently produces other FDA
regulated products and, therefore, has experience with FDA regulations,
(2) the nature and number of ASR's produced, (3) the size of the firm,
and (4) the adequacy of the firm's existing quality control procedures.
a. Registration and listing. The majority of manufacturers and
suppliers of ASR's will incur a small cost to register and list their
products with the agency. For manufacturers familiar with this
requirement, the average time estimated to comply with the registration
and listing requirement is 0.8 hour per year. For those manufacturers
that do not currently produce any FDA regulated products, the initial
registration and listing may require up to 2 hours of time (a
combination of management and clerical time). If half of the estimated
300 manufacturers and suppliers have previous FDA experience, the
estimated number of hours to comply with this requirement in the first
year will be a maximum of 420 hours for a total industry cost of
$9,555. In recurring years, registration and listing will require a
total of 240 hours for an industry cost of $5,460 per year.
b. CGMP and MDR compliance. The actual costs of instituting CGMP
and MDR procedures will vary greatly and, among other things, depend on
the number and nature of the products produced, the size of the firm,
and the nature of its current quality control system. FDA believes that
the majority of firms have many of the necessary quality control
procedures in place. However, for the smaller percentage of firms that
do not currently have CGMP and MDR procedures in place, the cost of
compliance with these two rules can be significant.
To comply with the CGMP regulation, manufactures will need to write
and implement standard operating procedures for their operation,
perform appropriate validation, train their employees, and develop,
implement, and maintain procedures for reporting deaths and serious
injuries related to their products. There will be additional
documentation costs on an annual, recurring basis, and some firms may
have to hire an additional person to perform the quality assurance
function. Firms without FDA experience and those with limited
regulatory staff may hire an industry consultant to help them come into
compliance with this rule.
FDA believes that the majority of firms have experience producing
FDA-related products. However, for the smaller number of firms that
have little
[[Page 62257]]
or no experience producing FDA-regulated products, that have limited
quality control procedures, and that could require the help of a
consultant to assist with CGMP compliance, the one-time costs range
from $50,000 to $200,000 depending on the number of products produced
and the size of the firm. In addition, firms that must hire a quality
assurance manager may incur costs of $40,000 to $50,000 per year in
additional salary and documentation costs. Alternatively, firms that
produce other medical devices under the CGMP regulations would incur
much smaller costs because they would expand their current procedures
to include ASR production. FDA cannot estimate the total economic
impact of these two requirements because the agency does not know how
many of the firms that produce ASR's also produce other regulated
medical devices. The agency believes, however, that the majority of the
manufacturers affected by this rule also produce other medical devices
and/or have many of the necessary quality control procedures in place.
These firms will incur costs significantly lower than the $50,000 to
$200,000 estimated above.
c. Class II and III ASR's. A small subset of ASR's are classified
as Class II or III devices. In addition to the general controls, these
products will also be subject to special controls. To market these
ASR's, manufacturers or suppliers must have an approved 510(k) for a
class II device or a PMA for a class III device. Because FDA will
review the performance of these ASR's with the test for which it is a
component, the agency believes that these ASR's will not be marketed as
independent components. Manufacturers of these ASR's are either
currently marketing them to kit manufacturers or are themselves
manufacturing the kits or tests that already have approved 510(k)'s or
PMA's for marketing. Thus, no costs were estimated for this
requirement.
d. Labeling. FDA is allowing manufacturers and suppliers up to 1
year to deplete current labeling stock before requiring compliance with
the labeling requirements. All ASR manufacturers or suppliers must
review their labeling, including promotional materials, to ascertain
compliance with the new labeling requirements. The agency believes
that, except for those ASR's sold to in vitro diagnostic manufacturers,
almost all ASR's will require relabeling. The economic impact of this
requirement is the one-time cost of redesigning and reviewing the new
labeling. The agency estimates that the cost to redesign the label is
$89.50 (1 hour to redesign the label, 3 hours of middle management
review) and the cost to redesign promotional materials is $115.50 (1
hour to redesign materials and 4 hours to review). Because
manufacturers have not been required to list their products with the
agency, FDA does not know how many ASR products are sold to clinical
laboratories. Industry experts estimate that between 5,000 and 10,000
ASR's are marketed. Assuming there are 7,500 ASR products, the total
cost to redesign both labels and promotional materials is $1.5 million
($671,250 for labels, $866,250 for promotional materials) or $205 per
product. The impact on an individual firm will depend on the number of
products produced.
e. Restriction of sales. This rule restricts the sale of ASR's for
clinical use to laboratories certified to perform high complexity
testing under CLIA. HCFA estimates that there are approximately 57,000
accredited and certified laboratories in the United States. Because of
the large number of laboratories, the agency believes this restriction
will have no economic impact on the industry. FDA received no comments
to the proposed rule that suggested otherwise.
2. Impact on Clinical Laboratories
Clinical laboratories that develop in-house tests using ASR's will
be required to inform the person ordering the tests that these tests
were not cleared or approved by FDA. In addition, ordering of such
tests is limited to physicians and other persons authorized by
applicable State law. FDA believes the economic impact of these two
requirements on clinical laboratories will be minimal. As discussed
earlier in this preamble in section III.A.4 of this document, the
disclaimer is not inconsistent with existing CLIA requirements. In
addition, both state laws and current industry practice limit the
access of testing to trained professionals. Moreover, no comments were
received with regard to either of these requirements suggesting that
they would increase the economic burden on clinical laboratories. Since
FDA has not mandated the specific means by which clinical laboratories
must comply with the disclosure statement requirement, laboratories
that produce computer generated reports may choose to reprogram to add
the statement, to order preprinted report forms, or to order a stamp.
FDA estimates a one-time cost of about $80 per establishment. However,
because FDA does not know how many clinical laboratories develop and
use in-house tests using ASR's, the agency cannot estimate the total
industry impact of this requirement.
D. Analysis of Alternatives
The agency considered a number of alternatives in developing the
proposal and this final rule. The rejected alternatives would have
created a greater economic burden on industry without an appreciable
increase in public health or safety. The agency considered: (1)
Enforcing its statutory authority and regulating all postamendment
ASR's as class III devices subject to the premarket approval
procedures, (2) classifying a greater number of ASR's as class II or
III devices, and (3) requiring premarket notification for all class I
ASR's. These alternatives, which were discussed in the preambles to the
proposed and final rules, were rejected because the agency determined
that for the majority of ASR's (the class I products) general controls
would be sufficient to ensure that ASR's are of consistent quality and
have appropriate labeling. As a result, the agency believes that the
current rule is the least burdensome alternative that meets the
agency's public health goal.
E. Response to Comments Concerning Small Business
The major concern of small business with regard to the economic
impact of this rule is the cost of complying with the CGMP regulation.
One comment suggested that the CGMP regulation should not be applied to
small companies. Another suggested that small companies would be at a
competitive disadvantage to large firms, suggesting that large firms
could pass through any increase in compliance costs, while small firms
would be unable to afford the initial costs of developing CGMP's.
As a rule, the nature of a firm's existing quality system will be
the major determinant of the cost of compliance with the CGMP
regulation. The more comprehensive a firm's quality system and the more
closely it resembles the CGMP, the easier it will be for a firm to
adapt its current practice. The agency recognizes that for some firms
with limited quality control systems and no experience manufacturing
FDA regulated products, the cost of developing CGMP's can be
significant. These costs would vary directly, although not
proportionally, with the size of the firm. Smaller firms tend to have
fewer products and, thus, need to develop fewer procedures and
controls. They also have fewer employees to train. Larger firms are
more likely than very small firms to currently manufacture other
medical devices already subject to CGMP's. Such firms would have
proportionately lower
[[Page 62258]]
compliance costs. FDA recognizes that some of the firms that sell only
a small percentage of their products to the clinical laboratory market
may choose not to comply with the CGMP regulation and sell their
products only to manufacturers of IVD tests or kits, or to research
laboratories. The agency believes, however, that this will have no
significant effect on the supply of ASR's to clinical laboratories.
To reduce the burden on industry, FDA has delayed the effective
date for required CGMP compliance to 1 year after the date of
publication of this final rule and allowed the industry time to deplete
current stock of labeling. In addition, the agency has taken steps
specifically to assist small businesses with compliance through the
Division of Small Manufacturers Assistance (DSMA). DSMA provides
guidance documents through the FDA's World Wide Web site (http://
www.fda.gov) and fax-on-demand system (800-899-0381 or 301-827-0111),
as well as participating in agency and industry sponsored workshops,
conferences, and meetings to inform and assist businesses with
compliance issues. In particular ``The Medical Device Quality Systems
Manual: A Small Entity Compliance Guide,'' available on the web site,
provides examples of procedures and forms that can be adopted and
modified by manufacturers to reduce their cost of compliance.
F. Summary
Because the firms that would be affected by this regulation are not
currently required to register or list their ASR products, FDA cannot
make a precise estimate of the total cost of this rule. The greatest
cost, however, would be to facilities that are not currently subject to
any CGMP's. FDA does not know how many firms would fall into this
category, but even if all of the affected facilities needed to
implement such requirements for the first time, the cost of the rule
would be far below the $100 million threshold that determines an
economically significant regulation under Executive Order 12866 or the
Unfunded Mandate Reform Act. For some individual firms, the economic
impact of this rule will be significant, but because the agency lacks
an accurate profile of the industry, it can not determine if a
substantial number of firms will be significantly affected.
VI. Environmental Impact
FDA has determined under 21 CFR 25.34(b) that this action is of the
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
VII. The Paperwork Reduction Act of 1995
A. Comments on the Paperwork Reduction Act Statement
One comment stated that the estimate in the proposed rule of
additional recordkeeping requirements was not accurate because the
estimate did not account for the burden resulting from registration,
listing, medical device reporting or application of the CGMP's. The
comment also stated that FDA should not establish a certification
program to demonstrate compliance with proposed restrictions.
FDA agrees that the estimate did not contain the burden for
registration, listing, medical device reporting, or application of
CGMP's. The registration, listing, medical device reporting collections
of information have already been approved by OMB (OMB control number
0910--0059). On October 7, 1996, FDA published the CGMP final rule (61
FR 52602) and provided a 60-day comment period to submit written
comments to FDA on the information collection provisions of the rule as
required under the Paperwork Reduction Act of 1995. A notice soliciting
comments for an additional 30 days on these provisions is under
development. These burdens were not included in the chart because any
CGMP, medical device reporting, registration and listing requirements
have already been estimated separately.
Neither the proposed nor the final rule contain a certification
requirement. Questions concerning certification are addressed in
section III.F. of this document.
B. Information Collection Provisions in the Final Rule
This final rule contains information collection provisions that are
subject to review by OMB under the Paperwork Reduction Act of 1995 (44
U.S. 3501-3520). OMB did not approve FDA's information collection
submitted to OMB with the proposed rule. The title, description and
respondent description of the information collection requirements are
shown below with an estimate of the annual reporting burden. Included
in the estimate is the time for reviewing instructions, gathering and
maintaining the data needed, and completing and reviewing the
collection of information.
Title: Labeling Requirements for Analyte Specific Reagents--
Labeling for Laboratories.
Description: The final rule amends the labeling requirements for
certain in vitro diagnostic products to require that manufacturers of
analyte specific reagents provide certain information concerning the
reagents to laboratories that will use the reagents to develop tests
for clinical use. The final regulation will also require that
advertising and promotional material for analyte specific reagents
include information about the identity and purity of the reagents and
not make any claims about analytic or clinical performance. The purpose
of the regulation is to assure that laboratories developing tests using
these reagents have sufficient information about their identity and
purity.
Description of Respondents: Businesses and other for profit
organizations.
Table 1.--Estimated Annual Reporting Burden
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Respondents Response Responses Response
----------------------------------------------------------------------------------------------------------------
809.10(e) 300 1 300 25 7,500
809.30(d) 300 1 300 25 7,500
Total 50 15,000
----------------------------------------------------------------------------------------------------------------
The proposed rule provided a 30-day comment period. As discussed
previously, the revised burden hour estimates in the final rule are
based partially on comments received. FDA has submitted the information
collection provisions of the final rule to OMB for review. Prior to the
effective date of this final rule, FDA will publish a notice in the
Federal Register of OMB's decision to approve, modify, or disapprove
the information collection
[[Page 62259]]
provisions. An agency may not conduct or sponsor, and a person is not
required to respond to, a collection of information unless it displays
a currently valid OMB control number.
List of Subjects
21 CFR Part 809
Labeling, Medical devices.
21 CFR Part 864
Blood, Medical devices, Packaging and containers.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts
809 and 864 are amended as follows:
PART 809--IN VITRO DIAGNOSTIC PRODUCTS FOR HUMAN USE
1. The authority citation for 21 CFR part 809 continues to read as
follows:
Authority: 21 U.S.C. 331, 351, 352, 355, 357, 360b, 360c, 360d,
360h, 360i, 360j, 371, 372, 374, 381.
2. Section 809.10 is amended in paragraph (a) by adding at the end
of the first sentence ``or as provided in paragraph (e) of this
section'' and by adding new paragraph (e) to read as follows:
Sec. 809.10 Labeling for in vitro diagnostic products.
* * * * *
(e)(1) The labeling for analyte specific reagents (e.g., monoclonal
antibodies, deoxyribonucleic acid (DNA) probes, viral antigens,
ligands) shall bear the following information:
(i) The proprietary name and established name (common or usual
name), if any, of the reagent;
(ii) A declaration of the established name (common or usual name),
if any;
(iii) The quantity, proportion, or concentration of the reagent
ingredient; and for a reagent derived from biological material, the
source and where applicable, a measure of its activity. The quantity,
proportion, concentration, or activity shall be stated in the system
generally used and recognized by the intended user, e.g., metric,
international units, etc.;
(iv) A statement of the purity and quality of the reagent,
including a quantitative declaration of any impurities present and
method of analysis or characterization. The requirement for this
information may be met by a statement of conformity with a generally
recognized and generally available standard that contains the same
information, e.g., those established by the American Chemical Society,
U.S. Pharmacopeia, National Formulary, and National Research Council.
The labeling may also include information concerning chemical/molecular
composition, nucleic acid sequence, binding affinity, cross-
reactivities, and interaction with substances of known clinical
significance;
(v) A statement of warnings or precautions for users as established
in the regulations contained in 16 CFR part 1500 and any other warnings
appropriate to the hazard presented by the product;
(vi) The date of manufacture and appropriate storage instructions
adequate to protect the stability of the product. When applicable,
these instructions shall include such information as conditions of
temperature, light, humidity, date of expiration, and other pertinent
factors. The basis for such instructions shall be determined by
reliable, meaningful, and specific test methods, such as those
described in Sec. 211.166 of this chapter;
(vii) A declaration of the net quantity of contents, expressed in
terms of weight or volume, numerical count, or any combination of these
or other terms that accurately reflect the contents of the package. The
use of metric designations is encouraged, wherever appropriate;
(viii) The name and place of business of manufacturer, packer, or
distributor;
(ix) A lot or control number, identified as such, from which it is
possible to determine the complete manufacturing history of the
product;
(x) For class I exempt ASR's, the statement: ``Analyte Specific
Reagent. Analytical and performance characteristics are not
established''; and
(xi) For class II and III ASR's, the statement: ``Analyte Specific
Reagent. Except as a component of the approved/cleared test (Name of
approved/cleared test), analytical and performance characteristics of
this ASR are not established.''
(2) In the case of immediate containers too small or otherwise
unable to accommodate a label with sufficient space to bear all such
information, and which are packaged within an outer container from
which they are removed for use, the information required by paragraphs
(e)(1) through (e)(6) of this section may appear in the outer container
labeling only.
3. New Sec. 809.30 is added to subpart C to read as follows:
Sec. 809.30 Restrictions on the sale, distribution and use of analyte
specific reagents.
(a) Analyte specific reagents (ASR's) (Sec. 864.4020 of this
chapter) are restricted devices under section 520(e) of the Federal
Food, Drugs, and Cosmetic Act (the act) subject to the restrictions set
forth in this section.
(b) ASR's may only be sold to:
(1) In vitro diagnostic manufacturers;
(2) Clinical laboratories regulated under the Clinical Laboratory
Improvement Amendments of 1988 (CLIA), as qualified to perform high
complexity testing under 42 CFR part 493 or clinical laboratories
regulated under VHA Directive 1106 (available from Department of
Veterans Affairs, Veterans Health Administration, Washington, DC
20420); and
(3) Organizations that use the reagents to make tests for purposes
other than providing diagnostic information to patients and
practitioners, e.g., forensic, academic, research, and other
nonclinical laboratories.
(c) ASR's must be labeled in accordance with Sec. 809.10(e).
(d) Advertising and promotional materials for ASR's:
(1) Shall include the identity and purity (including source and
method of acquisition) of the analyte specific reagent and the identity
of the analyte;
(2) Shall include the statement for class I exempt ASR's: ``Analyte
Specific Reagent. Analytical and performance characteristics are not
established'';
(3) Shall include the statement for class II or III ASR's:
``Analyte Specific Reagent. Except as a component of the approved/
cleared test (name of approved/cleared test), analytical and
performance characteristics are not established''; and
(4) Shall not make any statement regarding analytical or clinical
performance.
(e) The laboratory that develops an in-house test using the ASR
shall inform the ordering person of the test result by appending to the
test report the statement: ``This test was developed and its
performance characteristics determined by (Laboratory Name). It has not
been cleared or approved by the U.S. Food and Drug Administration.''
This statement would not be applicable or required when test results
are generated using the test that was cleared or approved in
conjunction with review of the class II or III ASR.
(f) Ordering in-house tests that are developed using analyte
specific reagents is limited under section 520(e) of the act to
physicians and other persons authorized by applicable State law to
order such tests.
(g) The restrictions in paragraphs (c) through (f) of this section
do not apply when reagents that otherwise meet the analyte specific
reagent definition are sold to:
[[Page 62260]]
(1) In vitro diagnostic manufacturers; or
(2) Organizations that use the reagents to make tests for purposes
other than providing diagnostic information to patients and
practitioners, e.g., forensic, academic, research, and other
nonclinical laboratories.
PART 864--HEMATOLOGY AND PATHOLOGY DEVICES
4. The authority citation for 21 CFR part 864 continues to read as
follows:
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 371.
5. Section 864.4010 is amended by revising paragraph (a) to read as
follows:
Sec. 864.4010 General purpose reagent.
(a) A general purpose reagent is a chemical reagent that has
general laboratory application, that is used to collect, prepare, and
examine specimens from the human body for diagnostic purposes, and that
is not labeled or otherwise intended for a specific diagnostic
application. It may be either an individual substance, or multiple
substances reformulated, which, when combined with or used in
conjunction with an appropriate analyte specific reagent (ASR) and
other general purpose reagents, is part of a diagnostic test procedure
or system constituting a finished in vitro diagnostic (IVD) test.
General purpose reagents are appropriate for combining with one or more
than one ASR in producing such systems and include labware or
disposable constituents of tests; but they do not include laboratory
machinery, automated or powered systems. General purpose reagents
include cytological preservatives, decalcifying reagents, fixative and
adhesives, tissue processing reagents, isotonic solutions and pH
buffers. Reagents used in tests for more than one individual chemical
substance or ligand are general purpose reagents (e.g., Thermus
aquaticus (TAQ) polymerase, substrates for enzyme immunoassay (EIA)).
* * * * *
6. New Sec. 864.4020 is added to subpart E to read as follows:
Sec. 864.4020 Analyte specific reagents.
(a) Identification. Analyte specific reagents (ASR's) are
antibodies, both polyclonal and monoclonal, specific receptor proteins,
ligands, nucleic acid sequences, and similar reagents which, through
specific binding or chemical reaction with substances in a specimen,
are intended for use in a diagnostic application for identification and
quantification of an individual chemical substance or ligand in
biological specimens. ASR's that otherwise fall within this definition
are not within the scope of subpart E of this part when they are sold
to:
(1) In vitro diagnostic manufacturers; or
(2) Organizations that use the reagents to make tests for purposes
other than providing diagnostic information to patients and
practitioners, e.g., forensic, academic, research, and other
nonclinical laboratories.
(b) Classification. (1) Class I (general controls). Except as
described in paragraphs (b)(2) and (b)(3) of this section, these
devices are exempt from the premarket notification requirements in part
807, subpart E of this chapter.
(2) Class II (special controls/guidance documents), when the
analyte is used in blood banking tests that have been classified as
class II devices (e.g., certain cytomegalovirus serological and
treponema pallidum nontreponemal test reagents). Guidance Documents:
1. ``Specifications for Immunological Testing for Infectious
Disease; Approved Guideline,'' NCCLS Document I/LA18-A, December
1994.
2. ``Assessment of the Clinical Accuracy of Laboratory Tests
Using Receiver Operating Characteristic (ROC) Plots; Tentative
Guideline,'' NCCLS Document KGP10-T, December 1993.
3. ``Review Criteria for Assessment of In Vitro Diagnostic
Devices for Direct Detection of Mycobacterium spp,'' FDA, July 6,
1993, and its ``Attachment 1,'' February 28, 1994.
4. ``Draft Review Criteria for Nucleic Acid Amplification-Based
In Vitro Diagnostic Devices for Direct Detection of Infectious
Microorganisms,'' FDA, July 6, 1993.
5. The Center for Biologics Evaluation and Research, FDA,
``Points to Consider in the Manufacture and Clinical Evaluation of
In Vitro Tests to Detect Antibodies to the Human Immunodeficiency
Virus, Type I'' (54 FR 48943, November 28, 1989).
(3) Class III (premarket approval), when:
(i) The analyte is intended as a component in a test intended for
use in the diagnosis of a contagious condition that is highly likely to
result in a fatal outcome and prompt, accurate diagnosis offers the
opportunity to mitigate the public health impact of the condition
(e.g., human immunodeficiency virus (HIV/AIDS)or tuberculosis (TB)); or
(ii) The analyte is intended as a component in a test intended for
use in donor screening for conditions for which FDA has recommended or
required testing in order to safeguard the blood supply or establish
the safe use of blood and blood products (e.g., tests for hepatitis or
tests for identifying blood groups).
(c) Date of 510(k), or date of PMA or notice of completion of a
product development protocol is required. (1) Preamendments ASR's; No
effective date has been established for the requirement for premarket
approval for the device described in paragraph (b)(3) of this section.
See Sec. 864.3.
(2) For postamendments ASR's; November 23, 1998.
(d) Restrictions. Restrictions on the sale, distribution and use of
ASR's are set forth in Sec. 809.30 of this chapter.
Dated: November 13, 1997.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 97-30334 Filed 11-20-97; 8:45 am]
BILLING CODE 4160-01-F
