[Federal Register Volume 74, Number 202 (Wednesday, October 21, 2009)]
[Rules and Regulations]
[Pages 53883-53885]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-25315]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 862

[Docket No. FDA-2009-N-0472]


Medical Devices; Clinical Chemistry and Clinical Toxicology 
Devices; Classification of the Cardiac Allograft Gene Expression 
Profiling Test Systems

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the 
classification of cardiac allograft gene expression profiling test 
systems 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: Cardiac Allograft Gene Expression 
Profiling Test Systems.'' FDA classified the device into class II 
(special controls) in order to provide a 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 November 20, 2009. The 
classification was effective August 26, 2008.

FOR FURTHER INFORMATION CONTACT: Kellie B. Kelm, Center for Devices and 
Radiological Health, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 66, rm. 5625, Silver Spring, MD 20993, 301-796-6145.

SUPPLEMENTARY INFORMATION:

I. Background

    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 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) of FDA's regulations.
    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 this classification (section 
513(f)(2) of the act).
    In accordance with section 513(f)(1) of the act, FDA issued an 
order on August 8, 2008, classifying the XDx AlloMap Test in 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. On August 15, 2008, 
XDx, Inc., submitted a petition requesting

[[Page 53884]]

classification of the AlloMap Test under section 513(f)(2) of the act. 
The manufacturer recommended that the device be classified into class 
II (Ref. 1).
    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). 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 AlloMap 
Test 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 ``Cardiac allograft gene 
expression profiling test system.'' It is identified as a device that 
measures the RNA expression level of multiple genes and combines this 
information to yield a signature (pattern, classifier, index, score) to 
aid in the identification of a low probability of acute cellular 
rejection (ACR) in heart transplant recipients with stable allograft 
function.
    FDA has identified the following issues of safety or effectiveness 
requiring special controls for a cardiac allograft gene expression 
profiling test system. Failure of this device to perform as indicated 
may lead to erroneous test results. False positive results will 
misclassify the patient into a higher risk group and false negative 
results will misclassify the patient into a lower risk group. 
Misclassification of ACR may lead to incorrect patient management with 
attendant psychological distress, inaccurate counseling, and suboptimal 
patient care.
    FDA believes the class II special controls guidance document 
generally addresses the risks to health identified in the previous 
paragraph and 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 510(k) premarket notification submission requirements for the 
device. FDA believes that the special controls, in addition to general 
controls, provide reasonable assurances of the safety and effectiveness 
of the device type. Therefore, on August 26, 2008, FDA issued an order 
to the petitioner classifying the device into class II (Ref. 2). FDA is 
codifying this classification by adding Sec.  862.1163.
    Any firm submitting a premarket notification submission for a 
cardiac allograft gene expression profiling test system 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) 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 notification is necessary to provide a reasonable assurance 
of the safety and effectiveness of the device and, therefore, this type 
of device is not exempt from premarket notification requirements. 
Persons who intend to market this type of device must submit to FDA a 
premarket notification, prior to marketing the device, which contains 
information about the cardiac allograft gene expression profiling test 
system they intend to market.

II. Environmental Impact

    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. Analysis of Impacts

    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 under 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 into 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 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 $133 million, using the most current (2008) 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. Federalism

    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. 21 
U.S.C. 360k; See Medtronic v. Lohr, 518 U.S. 470 (1996); Riegel v. 
Medtronic, 128 S. Ct. 999 (2008). The special controls established by 
this final rule create ``requirements'' for specific medical devices 
under 21 U.S.C. 360k, even though product sponsors have some 
flexibility in how they meet those requirements. See Papike v. 
Tambrands, Inc., 107 F.3d 737, 740-42 (9th Cir. 1997).

V. Paperwork Reduction Act of 1995

    This final rule establishes as special controls a guidance document 
that refers to previously approved collections of information found in 
other FDA regulations. These collections of information are subject to 
review by the Office of Management and

[[Page 53885]]

Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520) (the PRA). The collections of information in part 807, subpart E, 
regarding premarket notification submissions, have been approved under 
OMB Control No. 0910-0120. The collections of information in 21 CFR 
part 801 and 21 CFR 809.10, regarding labeling, have been approved 
under OMB Control No. 0910-0485. The collections of information in 21 
CFR part 820 have been approved under OMB Control No. 0910-0073.

VI. References

    The following references have 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 XDx, Inc., dated August 15, 2008.
    2. Order classifying XDx AlloMap Test, dated August 26, 2008.

List of Subjects in 21 CFR Part 862

    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 
862 is amended as follows:

PART 862--CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES

0
1. The authority citation for 21 CFR part 862 continues to read as 
follows:

    Authority:  21 U.S.C. 351, 360, 360c, 360e, 360j, 371.

0
2. Section 862.1163 is added to subpart B to read as follows:


Sec.  862.1163  Cardiac allograft gene expression profiling test 
system.

    (a) Identification. A cardiac allograft gene expression profiling 
test system is a device that measures the ribonucleic acid (RNA) 
expression level of multiple genes and combines this information to 
yield a signature (pattern, classifier, index, score) to aid in the 
identification of a low probability of acute cellular rejection (ACR) 
in heart transplant recipients with stable allograft function.
    (b) Classification. Class II (special controls). The special 
control is FDA's guidance document entitled ``Class II Special Controls 
Guidance Document: Cardiac Allograft Gene Expression Profiling Test 
Systems.'' See Sec.  862.1(d) for the availability of this guidance 
document.

    Dated: October 9, 2009.
Jeffrey Shuren,
Acting Director, Center for Devices and Radiological Health.
[FR Doc. E9-25315 Filed 10-20-09; 8:45 am]
BILLING CODE 4160-01-S