[Federal Register Volume 69, Number 189 (Thursday, September 30, 2004)]
[Proposed Rules]
[Pages 58371-58374]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 04-22009]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. 2003P-0564]
Microbiology Devices; Reclassification of Hepatitis A Virus (HAV)
Serological Assays (IgM Antibody, IgG Antibody and Total Antibodies
(IgM and IgG))
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to
reclassify hepatitis A virus (HAV) serological assays from Class III
(premarket approval) to class II (special controls). These devices are
used for testing specimens from individuals who have signs and symptoms
consistent with acute hepatitis A or for determining if an individual
has been previously infected with HAV. The detection of these
antibodies aids in the clinical laboratory diagnosis of an acute or
past infection by HAV in conjunction with other clinical laboratory
findings. FDA is proposing this action after reviewing a
reclassification petition submitted by Beckman Coulter, Inc. The agency
is taking this action under the Federal Food, Drug, and Cosmetic Act
(the act), as amended by the Medical Device Amendments of 1976 (the
1976 amendments), the Safe Medical Devices Act of 1990 (the SMDA), and
the Food and Drug Administration Modernization Act of 1997 (FDAMA).
Elsewhere in this issue of the Federal Register, FDA is announcing the
availability of a class II special controls draft guidance entitled
``Class II Special Controls Guidance Document: Hepatitis A Serological
Assays for the Clinical Laboratory Diagnosis of Hepatitis A Virus.''
DATES: Submit written or electronic comments by December 29, 2004. See
section VIII of this document for the proposed effective date of a
final rule based on this proposed rule.
ADDRESSES: Submit written comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
rm. 1061, Rockville, MD 20852. Submit electronic comments to http://
www.fda.gov/dockets/ecomments.
FOR FURTHER INFORMATION CONTACT: Sally Hojvat, Center for Devices and
Radiological Health (HFZ-440), Food and Drug Administration, 2098
Gaither Rd., Rockville, MD 20850, 301-594-2096.
SUPPLEMENTARY INFORMATION:
I. Background (Regulatory Authorities)
The act, as amended by the 1976 amendments (Public Law 94-295), the
SMDA (Public Law 101-629), and FDAMA (Public Law 105-115), 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 regulatory
controls needed to provide reasonable assurance of their safety and
effectiveness. The three categories of devices are class I (general
controls), class II (special controls), and class III (premarket
approval).
Under section 513 of the act, devices that were in commercial
distribution before May 28, 1976 (the date of enactment of the 1976
amendments), generally referred to as preamendments devices, are
classified after FDA has: (1) Received a recommendation from a device
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. FDA has classified most preamendments devices
under these procedures.
Devices that were not in commercial distribution prior to May 28,
1976, generally referred to as postamendments devices, are classified
automatically by statute (section 513(f) of the act) into class III
without any FDA rulemaking process. Those devices generally remain in
class III until the device is reclassified into class I or II, or FDA
issues an order finding the device to be substantially equivalent,
under section 513(i) of the act, to a legally marketed device. The
agency determines whether new devices are substantially equivalent to
previously offered devices by means of premarket notification
procedures in section 510(k) of the act (21 U.S.C. 360(k)) and part 807
(21 CFR part 807).
A preamendments device that has been classified into class III may
be marketed, by means of premarket notification procedures, without
[[Page 58372]]
submission of a premarket approval application (PMA) until FDA issues a
final regulation under section 515(b) of the act (21 U.S.C. 360e(b))
requiring premarket approval.
Section 513(f)(3) allows FDA to initiate reclassification of a
postamendments device classified into class III under section 513(f)(1)
of the act, or the manufacturer or importer of a device to petition the
Secretary of the Department of Health and Human Services for the
issuance of an order classifying the device in class I or class II.
FDA's regulations in Sec. 860.134 (21 CFR 860.134) set forth the
procedures for the filing and review of a petition for reclassification
of such class III devices. To change the classification of the device,
it is necessary that the proposed new classification have sufficient
regulatory controls to provide reasonable assurance of the safety and
effectiveness of the device for its intended use.
II. Regulatory History of the Device
HAV serological assays are used for testing specimens from
individuals who have signs and symptoms consistent with acute hepatitis
A or for determining if an individual has been previously infected with
HAV. The detection of these antibodies aids in the clinical laboratory
diagnosis of an acute or past infection by HAV in conjunction with
other clinical laboratory findings. These devices are postamendments
devices classified into class III under section 513(f)(1) of the act
and must be the subject of an approved PMA under section 515 of the act
before being placed into commercial distribution, unless they are
reclassified under section 513(f)(3) of the act.
In accordance with section 513(f)(3) of the act and Sec. 860.134,
Beckman Coulter, Inc., submitted a petition on October 1, 2003,
requesting reclassification of HAV antibody assays from class III to
class II.
III. Device Description
Hepatitis A virus serological assays are devices that consist of
antigens and antisera for the detection of hepatitis A virus-specific
immunoglobulin M (IgM), immunoglobulin G (IgG), or total antibodies
(IgM and IgG), in human serum or plasma (Refs. 1 and 2). These devices
are used for testing specimens from individuals who have signs and
symptoms consistent with acute hepatitis or for determining if an
individual has been previously infected with hepatitis A virus. The
detection of these antibodies aids in the clinical laboratory diagnosis
of an acute or past infection by the hepatitis A virus in conjunction
with other clinical laboratory findings. The presence of IgM type
antibodies differentiates an acute infection from past infection. These
devices are not intended for screening blood or solid or soft tissue
donors.
Currently marketed HAV serological assays typically are used on
automated laboratory analyzers, providing reportable results within 45
minutes. FDA has also approved assays based on manual enzyme-linked
immunosorbent assay (ELISA) and radioimmunoassay methods. Regardless of
method, these assays typically rely on specific binding of antibodies
to HAV and to fixed HAV antigen, which is then detected by a labeled
secondary (anti-IgM or anti-IgG) antibody. HAV specific IgM may also be
detected by the binding of human IgM to anti-human IgM bound to a solid
matrix. Labeled HAV antigen is then added and if specific anti-HAV has
been captured the antigen will bind. Serum and plasma are the common
matrices for currently marketed assays for HAV antibodies, as
antibodies reside physiologically in the liquid portion of the blood,
and are therefore reliably detected there or in plasma. Currently,
World Health Organization (WHO) material standards are available for
standardization of anti-HAV assays (Refs. 3 and 4).
IV. Proposed Reclassification
The agency is proposing to reclassify HAV serological assays from
class III to class II and has developed a guidance document which, when
final, will serve as the special control. Elsewhere in this issue of
the Federal Register, FDA is announcing the availability of this draft
guidance for comment in accordance with FDA's good guidance practices
(GGPs) regulation (21 CFR 10.115). We have determined that there is
adequate valid scientific evidence in the public domain to support this
reclassification action and, therefore, it was unnecessary to refer the
petition to a classification panel for its review and recommendation.
V. Risks to Health
There are no known direct risks to an individual's health
associated with the device. However, failure of HAV serological assays
to perform as indicated or an error in interpretation of results may
lead to improper patient management. There are no clinical features
that distinguish HAV infection from infection by other etiologic agents
of hepatitis such as the hepatitis B virus or hepatitis C virus. HAV
serological assays are used to aid in this distinction. Therefore,
false test results could contribute to misdiagnosis and improper
patient management.
A false negative measurement with failure to detect HAV-specific
IgM would misdiagnose an active HAV infection. False negative HAV
serological assay results may place individuals infected with
preexisting liver disease at risk for not receiving appropriate
therapy. It has been shown that HAV infection in individuals with
preexisting liver disease, e.g., HCV infection, has been associated
with an increased rate of fulminant hepatitis and mortality (Refs. 5 to
7). The administration of HAV-specific hyperimmune globulin may help to
prevent or improve the clinical manifestations of disease if given
within 2 weeks of infection as prophylaxis, although it is generally
not helpful in the acute phase of HAV infection (Ref. 8). In healthy
individuals, HAV infections are generally self-limiting without serious
consequences, with no chronic or persistent hepatitis (Ref. 9). The
failure to detect HAV-specific total or IgG antibodies would result in
misdiagnosis of past infection and may cause individuals to erroneously
receive vaccination for HAV. It is believed that this would be of
minimal risk because there is currently no contraindication for an
individual immune to HAV receiving HAV vaccination.
A false positive measurement can result in incorrect diagnosis of
active or past HAV infection. If HAV-specific total antibodies are
detected erroneously, an individual may not receive the vaccine for
HAV, and could continue to be at risk for HAV infection. A false
positive anti-HAV IgM result also has public health considerations
because the majority of state health departments are required to
followup reported acute HAV infections. This would place an undue
burden on state health department resources.
VI. Special Controls
In addition to general controls, FDA believes that the draft
guidance entitled ``Class II Special Controls Guidance Document:
Hepatitis A Serological Assays for the Clinical Laboratory Diagnosis of
Hepatitis A Virus'' is an adequate special control to address the risk
to health described above. Following the effective date of this final
classification rule, any firm submitting a 510(k) premarket
notification for Hepatitis A Virus (HAV) serological assays will need
to address the issues covered in the special controls guidance.
However, the firm need only show that its device meets the
recommendations of the guidance or in some other way provides
equivalent assurance of safety and effectiveness.
[[Page 58373]]
The class II special controls guidance provides information on how
to meet premarket (510(k)) submission requirements for the assays in
sections that discuss performance characteristics and labeling. The
performance characteristics section describes studies integral to
demonstration of appropriate performance and control against assays
that may fail to perform to current standards. The labeling section
addresses factors such as directions for use, quality control and
precautions for use and interpretation. FDA tentatively believes that
complying with the act and regulations and following the special
controls guidance document will provide reasonable assurance of safety
and effectiveness of these devices and adequately address the risk to
health identified in section V of this document.
VII. FDA's Tentative Findings
The efficacy of diagnosis of HAV by HAV antibody detection has been
well-established over the past 25 years. HAV antibody detection plays a
key role in diagnosis of HAV infection, because there are no other
approved clinical or laboratory methods that are specific for HAV
infection. Technological improvements have increased the reliability
and clinical sensitivity and specificity of performance of these
devices. A technologically improved enzyme-linked immunosorbent assay
(ELISA) format, new detection methodology, and the advent of monoclonal
antibody technology have enhanced the sensitivity and specificity of
the assays without introducing confounding issues (Ref. 10).
FDA has considered issues that could potentially complicate use or
interpretation of HAV antibody assay results. There do not appear to be
notable concerns for use and interpretation of HAV antibody assays
because most assays are now automated, HAV infection is primarily self-
limiting, and there are no specific treatment measures for HAV
infection. In addition, a WHO material reference for HAV antibodies is
available and assays from different manufacturers should be expected to
report similarly due to standardization to this material (Refs. 3 and
4) . Because HAV antibody assays are currently the only approved
specific diagnostic for HAV infection, the guidance recommends that
assay results only be interpreted in the context of other laboratory
findings and the total clinical status of the patient.
The FDAMA added section 510(m) to the act (21 U.S.C. 360(m)).
Section 510(m) of the act provides that a class II device may be
exempted from the premarket notification requirements under section
510(k) of the act (21 U.S.C. 360(k)), if the agency determines that
premarket notification is not necessary to provide reasonable assurance
of the safety and effectiveness of the device. For this type of device,
FDA has determined that premarket notification is necessary to provide
reasonable assurance of safety and effectiveness and, therefore, the
device is not exempt from the premarket notification requirements. FDA
review of performance characteristics will provide reasonable assurance
that acceptable levels of performance for both safety and effectiveness
are addressed before marketing clearance. Thus, persons who intend to
market this device must submit to FDA a premarket notification
submission containing information on HAV antibody detection assays
before marketing the device.
VIII. Effective Date
FDA proposes that any final regulation that may issue based on this
proposal become effective 30 days after its date of publication in the
Federal Register.
IX. Environmental Impact
The agency has determined that under 21 CFR 25.34(b) that this
reclassification action is of a type that does not individually or
cumulatively have a significant effect on the human environment.
Therefore, neither an environmental assessment nor an environmental
impact statement is required.
X. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this proposed rule is not a significant regulatory action as defined by
the Executive order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because reclassification of the device from class
III to class II will relieve manufacturers of the cost of complying
with the premarket approval requirements of section 515 of the act and
may permit small potential competitors to enter the marketplace by
lowering their costs, the agency certifies that the proposed rule will
not have a significant economic impact on a substantial number of small
entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $110 million. FDA does not expect this proposed rule
to result in any 1-year expenditure that would meet or exceed this
amount.
XI. Paperwork Reduction Act of 1995
FDA tentatively concludes that this proposed rule contains no new
collections of information. Therefore, clearance by the Office of
Management and Budget under the Paperwork Reduction Act of 1995 is not
required.
XII. Request for Comments and Proposed Dates
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this document.
Submit a single copy of electronic comments or two paper copies of any
mailed comments, except that individuals may submit one copy. Comments
are to be identified with the docket number found in brackets in the
heading of this document. Received comments may be seen in the Division
of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.
XIII. References
The following references have been placed on display in the
Division of Dockets Management (address above) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
1. Lemon, S.M., and N. Binn, ``Serum Neutralizing Antibody Response
to Hepatitis A Virus,'' Journal of Infectious Diseases, 14:1033-1039,
1983.
2. Lemon, S.M., ``Type A Viral Hepatitis: Epidemiology, Diagnosis,
and Prevention,'' Clinical Chemistry, 43:1494-1499, 1997.
3. WHO International Standard for anti-HAV Immunoglobulin; 2nd
International Standard 1998, WHO/BS/98.1878, 98.1878. Add. 1 (Cited in
WHO International Biological Reference
[[Page 58374]]
Preparations (Version 2001 Catalog, page 3 of 34 at: http://
www9.who.int/vaccines/Biologicals/KAlph.pdf)).
4. Ferguson, M., et al., ``Hepatitis A Immunoglobulin: an
International Collaborative Study to Establish the Second International
Standard,'' Biologicals, 28:233-240, 2000.
5. Devalle, S., V.S. de Paula, J.M. de Oliveira, et. al.,
``Hepatitis A virus infection in hepatitis C Brazilian patients,''
Journal of Infectious Diseases, August, 47(2):125-128, 2003.
6. Koff, R.S., ``Risks associated with hepatitis A and hepatitis B
in patients with hepatitis C,'' Journal of Clinical Gastroenerology,
July, 33(1):20-26, 2001.
7. Vento, S., ``Fulminant hepatitis associated with hepatitis A
virus superinfection in patients with chronic hepatitis C,'' Journal of
Viral Hepatitis, May; 7 Suppl 1:7-8, 2000.
8. Stapleton, J.T., ``Host immune response to hepatitis A virus,''
Journal of Infectious Diseases, 171(S1):S9-S14, 1995.
9. Hollinger, F.B. and S.U. Emerson, ``Hepatitis A Virus,'' in D.M.
Knipe et al., eds. Fields Virology, 4th ed. Lippincott Williams and
Wilkins, Philadelphia, 799-840, 2001.
10. Brown, E.A., and J.T. Stapleton, ``Hepatitis A Virus'' in P.R.
Murray et al., eds., Manual of Clinical Microbiology, 8th ed., ASM
Press, Washington, DC, 1452-1463, 2003.
List of Subjects in 21 CFR Part 866
Biologics, Laboratories, Medical devices.
0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
866 is proposed to be amended as follows:
PART 866-IMMUNOLOGY AND MICROBIOLOGY DEVICES
0
1. The authority citation for 21 CFR part 866 continues to read as
follows:
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 371.
0
2. Section 866.3310 is added to subpart D to read as follows:
Sec. 866.3310 Hepatitis A Virus (HAV) serological assays.
(a) Identification. Hepatitis A virus serological assays are
devices that consist of antigens and antisera for the detection of
hepatitis A virus-specific IgM, IgG, or total antibodies (IgM and IgG),
in human serum or plasma. These devices are used for testing specimens
from individuals who have signs and symptoms consistent with acute
hepatitis or for determining if an individual has been previously
infected with hepatitis A virus. The detection of these antibodies aids
in the clinical laboratory diagnosis of an acute or past infection by
hepatitis A virus in conjunction with other clinical laboratory
findings. These devices are not intended for screening blood or solid
or soft tissue donors.
(b) Classification. Class II (special controls). The special
control is ``Class II Special Controls Guidance Document: Hepatitis A
Serological Assays for the Clinical Laboratory Diagnosis of Hepatitis A
Virus.'' See Sec. 866.1(e) for the availability of this guidance
document.
Dated: September 21, 2004.
Linda S. Kahan,
Deputy Director, Center for Devices and Radiological Health.
[FR Doc. 04-22009 Filed 9-29-04; 8:45 am]
BILLING CODE 4160-01-S