[Federal Register: January 2, 2009 (Volume 74, Number 1)]
[Rules and Regulations]               
[Page 6-8]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr02ja09-4]                         

-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2008-N-0517]

 
Medical Devices; Immunology and Microbiology Devices; 
Classification of Enterovirus Nucleic Acid Assay

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is classifying 
enterovirus nucleic acid assay into class II (special controls). The 
special control that will apply to the device is the guidance document 
entitled ``Class II Special Controls Guidance Document: Nucleic Acid 
Amplification Assay for the Detection of Enterovirus RNA'' (ribonucleic 
acid). The agency is classifying the device into class II (special 
controls) in order to provide a

[[Page 7]]

reasonable assurance of safety and effectiveness of the device. 
Elsewhere in this issue of the Federal Register, FDA is announcing the 
availability of the guidance document that will serve as the special 
control for this device.

DATES:  This final rule is effective February 2, 2009. The 
classification was effective March 16, 2007.

FOR FURTHER INFORMATION CONTACT: Uwe Scherf, Center for Devices and 
Radiological Health (HFZ-440), Food and Drug Administration, 2098 
Gaither Rd., Rockville, MD 20850, 240-276-0725.

SUPPLEMENTARY INFORMATION:

I. What is the Background of This Rulemaking?

    In accordance with section 513(f)(1) of the Federal Food, Drug, and 
Cosmetic Act (the act) (21 U.S.C. 360c(f)(1)), devices that were not in 
commercial distribution before May 28, 1976, the date of enactment of 
the Medical Device Amendments of 1976 (the amendments), generally 
referred to as postamendments devices, are classified automatically by 
statute into class III without any FDA rulemaking process. These 
devices remain in class III and require premarket approval, unless and 
until the device is classified or reclassified into class I or II, or 
FDA issues an order finding the device to be substantially equivalent, 
in accordance with section 513(i) of the act, to a predicate device 
that does not require premarket approval. The agency determines whether 
new devices are substantially equivalent to predicate 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).
    Section 513(f)(2) of the act provides that any person who submits a 
premarket notification under section 510(k) of the act for a device 
that has not previously been classified may, within 30 days after 
receiving an order classifying the device in class III under section 
513(f)(1), request FDA to classify the device under the criteria set 
forth in section 513(a)(1). FDA shall, within 60 days of receiving such 
a request, classify the device by written order. This classification 
shall be the initial classification of the device. Within 30 days after 
the issuance of an order classifying the device, FDA must publish a 
notice in the Federal Register announcing such classification (section 
513(f)(2) of the act).
    In accordance with section 513(f)(1) of the act, FDA issued an 
order on March 9, 2007, classifying the Xpert EVTM Assay as 
class III, because it was not substantially equivalent to a device that 
was introduced or delivered for introduction into interstate commerce 
for commercial distribution before May 28, 1976, or a device that was 
subsequently reclassified into class I or class II. Cepheid submitted a 
petition dated March 9, 2007, requesting classification of the Xpert 
EVTM Assay under section 513(f)(2) of the act. FDA filed the 
petition on March 12, 2007. The manufacturer recommended that the 
device be classified into class II.
    In accordance with section 513(f)(2) of the act, FDA reviewed the 
petition in order to classify the device under the criteria for 
classification set forth in section 513(a)(1) of the act. Devices are 
to be classified into class II if general controls, by themselves, are 
insufficient to provide reasonable assurance of safety and 
effectiveness, but there is sufficient information to establish special 
controls to provide reasonable assurance of the safety and 
effectiveness of the device for its intended use. After review of the 
information submitted in the petition, FDA determined that the Xpert 
EVTM Assay can be classified in class II with the 
establishment of special controls. FDA believes these special controls, 
in addition to general controls, will provide reasonable assurance of 
safety and effectiveness of the device.
    The device is assigned the generic name ``enterovirus nucleic acid 
assay.'' It is identified as a device that consists of primers, probes, 
enzymes, and controls for the amplification and detection of 
enterovirus RNA in cerebrospinal fluid (CSF) from individuals who have 
signs and symptoms consistent with meningitis or meningoencephalitis. 
The detection of enterovirus RNA, in conjunction with other laboratory 
tests, aids in the clinical laboratory diagnosis of viral meningitis 
caused by enterovirus.
    Failure of nucleic acid assays for detection of enterovirus RNA to 
perform as expected, or failure to interpret results correctly, may 
lead to incorrect patient management decisions. A false negative report 
could lead to delays in providing (or even failure to provide) a 
definitive diagnosis, and the unnecessary treatment of the patient with 
antibiotics. A false positive report could lead to a delayed treatment 
of bacterial meningitis or other forms of meningitis. This delayed 
treatment due to a false positive result could cause progression of 
potentially life-threatening bacterial meningitis with subsequent 
severe morbidity to the patient and potentially even patient death. 
Device failure leading to no result (for example, due to failure of 
reagents, instrumentation, data management, or software) or an invalid 
or equivocal result could delay diagnosis, and could require an 
additional collection of CSF fluid, a procedure that is associated with 
the risk of infection. Furthermore, the appearance of new serotypes of 
enterovirus may affect the performance of an enterovirus nucleic acid 
amplification assay for the detection of enterovirus RNA in CSF 
specimens. Primers and probes for detection of enteroviruses are 
selected for their homology with highly conserved regions within viral 
RNA segments that are present in most enterovirus serotypes. Primers 
and probes might not detect new serotypes that appear over time. In 
addition, test performance can be affected, as the epidemiology and 
pathology of disease caused by the new enterovirus serotypes could 
change.
    FDA believes the class II special controls guidance document will 
aid in mitigating potential risks by providing recommendations on 
labeling and validation of performance characteristics. The guidance 
document also provides information on how to meet premarket (510(k)) 
submission requirements for the device. FDA believes that following the 
class II special controls guidance document generally addresses the 
risks to health identified in the previous paragraph. Therefore, on 
March 16, 2007, FDA issued an order to the petitioner classifying the 
device into class II. FDA is codifying this classification by adding 
Sec.  866.3225.
    Following the effective date of this final classification rule, any 
firm submitting a 510(k) premarket notification for an enterovirus 
nucleic acid assay 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.
    Section 510(m) of the act provides that FDA may exempt a class II 
device from the premarket notification requirements under section 
510(k) of the act, if FDA determines that premarket notification is not 
necessary to provide reasonable assurance of the safety and 
effectiveness of the device. For this type of device, however, FDA has 
determined that premarket review of the system's key performance 
characteristics, test methodology, labeling, and other requirements as 
outlined in Sec.  807.87, will provide reasonable assurance that 
acceptable levels of performance for both safety and effectiveness will 
be addressed before marketing clearance. Thus, persons who intend to 
market this type

[[Page 8]]

of device must submit to FDA a premarket notification, prior to 
marketing the device, which contains information about the gene 
expression profiling test system for breast cancer prognosis they 
intend to market.

II. What is the Environmental Impact of This Rule?

    The agency has determined under 21 CFR 25.34(b) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

III. What is the Economic Impact of This Rule?

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and 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 final 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 classification of this device type into 
class II will relieve manufacturers of the device of the cost of 
complying with the premarket approval requirements of section 515 of 
the act (21 U.S.C. 360e), and may permit small potential competitors to 
enter the marketplace by lowering their costs, the agency certifies 
that the final 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 $130 million, using the most current (2007) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.

IV. Does This Final Rule Have Federalism Implications?

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. Section 4(a) of the Executive order 
requires agencies to ``construe *** a Federal statute to preempt State 
law only where the statute contains an express preemption provision or 
there is some other clear evidence that the Congress intended 
preemption of State law, or where the exercise of State authority 
conflicts with the exercise of Federal authority under the Federal 
statute. Federal law includes an express preemption provision that 
preempts certain state requirements ``different from, or in addition 
to'' certain federal requirements applicable to devices. See 21 U.S.C. 
360k; Medtronic v. Lohr, 518 U.S. 470 (1996); Riegel v. Medtronic, 128 
S.Ct. 999 (2008).
    In this rulemaking, FDA has determined that general controls by 
themselves are insufficient to provide reasonable assurance of the 
safety and effectiveness of the device, and that there is sufficient 
information to establish special controls to provide such assurance. 
FDA has therefore imposed a special control to address the 
amplification and detection of enterovirus RNA in CSF from individuals 
who have signs and symptoms consistent with meningitis or 
meningoencephalitis. The detection of enterovirus RNA, in conjunction 
with other laboratory tests, aids in the clinical laboratory diagnosis 
of viral meningitis caused by enterovirus.
    As with any Federal requirement, if a State law requirement makes 
compliance with both Federal law and State law impossible, or would 
frustrate Federal objectives, the State requirement would be preempted. 
See Geier v. American Honda Co., 529 U.S. 861, (2000); English v. 
General Electric Co., 496 U.S. 72, 79 (1990), Florida Lime & Avocado 
Growers, Inc., 373 U.S. 132, 142-143 (1963); Hines v. Davidowitz, 312 
U.S. 52, 67 (1941).

V. How Does This Rule Comply With the Paperwork Reduction Act of 1995?

     This final rule contains no collections of information. Therefore, 
clearance by the Office of Management and Budget (OMB) under the 
Paperwork Reduction Act of 1995 is not required. Elsewhere in this 
issue of the Federal Register, FDA is issuing a notice announcing the 
guidance for the final rule. This guidance entitled ``Class II Special 
Controls Guidance Document: Nucleic Acid Amplification Assay for the 
Detection of Enterovirus RNA'' references previously approved 
collections of information found in FDA regulations.

VI. What References Are on Display?

    The following reference has been placed on display in the Division 
of Dockets Management (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, rm. 1061, Rockville, MD 20852, and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Petition from Cepheid, dated March 9, 2007.

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 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 866.3225 is added to subpart D to read as follows:


Sec.  866.3225   Enterovirus nucleic acid assay.

    (a) Identification. An enterovirus nucleic acid assay is a device 
that consists of primers, probes, enzymes, and controls for the 
amplification and detection of enterovirus ribonucleic acid (RNA) in 
cerebrospinal fluid (CSF) from individuals who have signs and symptoms 
consistent with meningitis or meningoencephalitis. The detection of 
enterovirus RNA, in conjunction with other laboratory tests, aids in 
the clinical laboratory diagnosis of viral meningitis caused by 
enterovirus.
    (b) Classification. Class II (special controls). The special 
control is FDA's guidance document entitled ``Class II Special Controls 
Guidance Document: Nucleic Acid Amplification Assay for the Detection 
of Enterovirus RNA.'' See Sec.  866.1(e) for the availability of this 
guidance document.

    Dated: December 16, 2008.
Daniel G. Schultz,
Director, Center for Devices and Radiological Health.
[FR Doc. E8-31213 Filed 12-31-08; 8:45 am]

BILLING CODE 4160-01-S