[Federal Register Volume 70, Number 46 (Thursday, March 10, 2005)]
[Rules and Regulations]
[Pages 11865-11867]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-4762]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 862

[Docket No. 2005N-0067]


Medical Devices; Clinical Chemistry and Clinical Toxicology 
Devices; Drug Metabolizing Enzyme Genotyping System

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is classifying drug 
metabolizing enzyme (DME) genotyping 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: Drug Metabolizing Enzyme Genotyping System.'' The agency is 
classifying 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 
publishing a notice of availability of a guidance document that is the 
special control for this device.

DATES: This rule is effective April 11, 2005. The classification was 
effective December 23, 2004.

FOR FURTHER INFORMATION CONTACT: Courtney Harper, Center for Devices 
and Radiological Health (HFZ-440), Food and Drug Administration, 2098 
Gaither Rd., Rockville, MD 20850, 240-276-0443, ext. 159.

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 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 previously marketed 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 such classification (section 
513(f)(2) of the act).
    In accordance with section 513(f)(1) of the act, FDA issued a 
notice on December 17, 2004, classifying the Roche Amplichip CYP450 
Test (2D6) 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 
to a device that was subsequently reclassified into class I or class 
II. On December 20, 2004, Roche Molecular Systems, Inc., submitted a 
petition requesting classification of the Roche Amplichip CYP450 Test 
(2D6) under section 513(f)(2) of the act. 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). 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 Roche 
Amplichip CYP450 Test (2D6) 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 ``drug metabolizing enzyme 
genotyping system.'' It is identified as a device intended for use in 
testing deoxyribonucleic acid (DNA) extracted from clinical samples to 
identify the

[[Page 11866]]

presence or absence of human genotypic markers encoding a DME. This 
device is used as an aid in determining treatment choice and 
individualizing treatment dose for therapeutics that are metabolized 
primarily by the specific enzyme about which the system provides 
genotypic information.
    FDA has identified the risks to health associated with this type of 
device as failure to correctly identify the DME genotype, which could 
result in incorrect patient management decisions. In these situations a 
patient might be prescribed an incorrect drug or drug dose with 
concomitant increased risk of adverse reactions due to increased or 
decreased drug metabolism. Likewise, failure to properly interpret 
genotyping results could lead to incorrect prediction of phenotype and 
result in incorrect patient management decisions. The information 
provided by this type of genetic test should only be used to supplement 
other tools for therapeutic decisionmaking in conjunction with routine 
monitoring by a physician.
    The effect that a specific DME allele has on drug metabolism may 
vary depending on the specific drug, even for drugs within a specific 
class. Effects of specific alleles on drug metabolism are well-
documented for some drugs; for other drugs, they are less well-
documented. Therefore, clinicians should use professional judgment when 
interpreting results from this type of test. In addition, results from 
this type of assay should not be used to predict a patient's response 
to drugs in cases where either (1) the DME activity of the allele has 
not been determined or (2) the drug's metabolic pathway has not been 
clearly established.
    The class II special controls guidance document also provides 
information on how to meet premarket (510(k)) submission requirements 
for the device, including recommendations on validation of performance 
characteristics and labeling. FDA believes that following the class II 
special controls guidance document generally addresses the risks to 
health identified above. Therefore, on December 23, 2004, FDA issued an 
order to the petitioner classifying the device into class II. FDA is 
codifying this classification by adding 21 CFR 862.3360.
    Following the effective date of this final classification rule, any 
firm submitting a 510(k) premarket notification for a DME genotyping 
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 reasonable assurance of 
safety and effectiveness. FDA review of performance characteristics, 
test methodology, and labeling to satisfy requirements of Sec.  
807.87(e), 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 of 
device must submit to FDA a premarket notification containing 
information on the DME genotyping system before marketing the device.

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 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 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 $115 million, using the most current (2003) 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. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

V. Paperwork Reduction Act of 1995

    This final rule contains no collections of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

VI. Reference

    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 Roche Molecular Systems, Inc., dated December 
20, 2004.

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:

[[Page 11867]]

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 862.3360 is added to subpart D to read as follows:


Sec.  862.3360  Drug metabolizing enzyme genotyping system.

    (a) Identification. A drug metabolizing enzyme genotyping system is 
a device intended for use in testing deoxyribonucleic acid (DNA) 
extracted from clinical samples to identify the presence or absence of 
human genotypic markers encoding a drug metabolizing enzyme. This 
device is used as an aid in determining treatment choice and 
individualizing treatment dose for therapeutics that are metabolized 
primarily by the specific enzyme about which the system provides 
genotypic information.
    (b) Classification. Class II (special controls). The special 
control is FDA's guidance document entitled ``Class II Special Controls 
Guidance Document: Drug Metabolizing Enzyme Genotyping Test System.'' 
See Sec.  862.1(d) for the availability of this guidance document.

    Dated: March 2, 2005.
Linda S. Kahan,
Deputy Director, Center for Devices and Radiological Health.
[FR Doc. 05-4762 Filed 3-9-05; 8:45 am]
BILLING CODE 4160-01-S