Document Headings

                    Document headings vary by document type but may contain                    the following:                  
                -                       the agency or agencies that issued and signed a document                    
                -                       the number of the CFR title and the number of each part                      the document amends, proposes to amend, or is directly                      related to                    
                -                       the agency docket number / agency internal file number                    
                -                       the RIN which identifies each regulatory action listed in                      the Unified Agenda of Federal Regulatory and Deregulatory                      Actions                    

                    See the                                          Document Drafting Handbook                                        for more details.                  

###### Department of Health and Human Services

###### Food and Drug Administration

          - 21 CFR Part 862
          - [Docket No. FDA-2009-N-0472]

# AGENCY:

Food and Drug Administration, HHS.

# ACTION:

Final rule.

# 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                           ( print 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 § 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                           ( print 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

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

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.

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

§ 862.1163

                            (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 § 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