[Federal Register Volume 69, Number 189 (Thursday, September 30, 2004)]
[Proposed Rules]
[Pages 58371-58374]
From the Federal Register Online via the Government Publishing 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availability of a class II special controls draft guidance entitled 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