[Federal Register Volume 62, Number 242 (Wednesday, December 17, 1997)]
[Rules and Regulations]
[Pages 66003-66005]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-32876]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. 95P-0136]


Medical Devices; Reclassification of Tumor-Associated Antigen 
Immunological Test Systems

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that it 
is codifying the reclassification of tumor-associated antigen 
immunological test systems intended as an aid in monitoring patients 
for disease progression or response to therapy or for the detection of 
recurrent or residual disease from class III (premarket approval) to 
class II (special controls). FDA is also announcing that it has issued 
an order in the form of a letter to Centocor, Inc., reclassifying serum 
tumor markers into class II. This action is being taken under the 
Federal Food, Drug, and Cosmetic Act (the act), as amended by the 
Medical Device Amendments of 1976 and the Safe Medical Devices Act of 
1990.

EFFECTIVE DATES: The reclassification was effective September 19, 1996. 
The codification becomes effective December 17, 1997.

FOR FURTHER INFORMATION CONTACT: Joseph M. Sheehan, Center for Devices

[[Page 66004]]

and Radiological Health (HFZ-215), Food and Drug Administration, 1350 
Piccard Dr., Rockville, MD 20850, 301-827-2974.

SUPPLEMENTARY INFORMATION:

I. Background

    On April 18, 1995, FDA filed a petition submitted by Centocor, 
Inc., requesting reclassification from class III to class II of tumor-
associated antigen immunological test systems, commonly called serum 
tumor markers, indicated for use in the monitoring of tumor-associated 
antigen levels in patient serum samples. The tumor-associated antigen 
immunological test system was a class III ``transitional'' device under 
section 520(l) of the act (21 U.S.C. 360j(l)). The petition, was 
seeking reclassification under the procedures set forth in section 
520(l)(2) of the act and 21 CFR 860.136 of the agency's regulations.
    FDA consulted with the Immunology Devices Panel (the Panel). During 
the open public meeting on December 1, 1995, the Panel recommended that 
FDA reclassify the tumor-associated antigen immunoassay systems for use 
in monitoring from class III to class II. It further recommended that 
those tumor markers used for screening indications remain in class III.
    Based on its consultation with the Panel, review of the data and 
information contained in the petition and presented before the Panel, 
published studies and professional standards, FDA concurred with the 
Panel's recommendation that tumor-associated antigen immunoassay 
systems should be reclassified from class III into class II with 
implementing special controls. FDA further concurred that markers used 
for screening indications will remain in class III.
    On September 19, 1996, FDA issued an order (Ref. 1) in the form of 
a letter to Centocor, Inc., reclassifying the generic type of device, 
tumor-associated antigen immunological test systems intended as an aid 
in monitoring patients for disease progression or response to therapy 
or for the detection of recurrent or residual disease, from class III 
to class II. The order identified the generic type of tumor-associated 
antigen immunological test system as a device that consists of the 
reagents used to qualitatively or quantitatively measure, by 
immunochemical techniques, tumor-associated antigens in serum, plasma, 
urine, or other body fluids. This generic type of device does not 
include tissue receptor assays, immunohistochemical stains, or direct 
tests for oncogenes or other genetic markers associated with a 
predisposition to development of certain cancers.
    Measurement of tumor-associated antigen levels aid in the 
monitoring of certain cancers. Monitoring is defined here as assessing 
disease progression, recurrence, or response to therapy. This includes 
the serial measurement of antigens in patients with histologically 
confirmed diagnoses who are undergoing therapy for residual or advanced 
disease. Increasing tumor marker concentrations are indicative of 
progressive disease, decreasing concentrations are indicative of 
response to therapy, and constant serial tumor marker concentrations 
are associated with a stable disease state. Monitoring is further 
defined as single or serial measurements used as an aid in the 
detection of recurrent or residual disease in patients following 
primary curative treatment. Sustained elevations in marker 
concentrations are suggestive of residual disease, whereas increasing 
concentrations are indicative of recurring disease.
    The order also identified FDA's designated special controls as a 
premarket notification, section 510(k) (21 U.S.C. 360(k)), guidance 
document for tumor-associated antigens (Ref. 2), and existing voluntary 
standards for assay performance by the National Committee for Clinical 
Laboratory Standards (the NCCLS) (Ref. 3). The guidance document 
provides the review criteria and data requirements for a 510(k) 
submission. The guidance document also provides suggestions for non-
clinical laboratory studies and the design, conduct, and analysis of 
appropriate clinical studies to support the performance of these 
devices. The NCCLS assay performance standards provide evaluative 
techniques to assure the accurate performance of the antigen tests. FDA 
believes that these special controls provide the necessary control to 
reasonably assure the safety and effectiveness of these devices.
    FDA notes that the risks associated with the use of tumor markers 
are relatively low in comparison to the benefits that result from their 
use for patient monitoring. Furthermore, the risks and benefits 
associated with the use of tumor markers in the practice of medical 
oncology are well understood by clinicians. The use and performance 
characteristics of these devices have been addressed in thousands of 
peer-review scientific reports and the evaluative techniques used to 
establish acceptable performance are well described and referenced in 
the special controls. Additionally, FDA has 20 years of scientific 
review experience to draw upon in the evaluation of new tumor markers, 
and believes that tumor antigen immunoassay systems are well 
characterized.
    Consistent with the act and the regulations, FDA is announcing that 
on September 19, 1996, an order in the form of a letter was sent to 
Centocor, Inc., reclassifying the generic type tumor-associated antigen 
immunoassay system that is intended as an aid in monitoring patients 
for disease progression or response to therapy or for the detection of 
recurrent or residual disease from class III to class II. Additionally, 
FDA is codifying the reclassification of this device, by amending 21 
CFR 866.6010.

II. Environmental Impact

    The agency has determined under 21 CFR 25.24(e)(2) 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 this final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612) (as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1996 (Pub. L. 104-121)), and the Unfunded Mandates Reform Act of 1995 
(Pub. L. 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 consistent with 
the regulatory philosophy and principles identified in the Executive 
Order. In addition, the final rule is not a significant regulatory 
action as defined by the Executive Order and so is not subject to 
review 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. Reclassification of this devices from class III to 
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 Commissioner of Food 
and Drugs, certifies that this final rule will not have a significant 
economic impact on a

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substantial number of small entities. This final rule also does not 
trigger the requirement for a written statement under section 202(a) of 
the Unfunded Mandates Reform Act because it does not impose a mandate 
that results in an expenditure of $100 million of more by State, local, 
or tribal governments in the aggregate, or by the private sector, in 
any 1 year.

IV. References

    The following references have been placed on display in the 
Dockets Management Branch (HFA-305), Food and Drug Administration, 
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857, and may be seen 
by interested persons between 9 a.m. and 4 p.m., Monday through 
Friday.
    1. FDA letter (order) to Centocor, Inc., dated September 19, 
1996.
    2. Guidance Document for the Submission of Tumor Associated 
Antigen Premarket Notifications (510(k)) to FDA, September 19, 1996.
    3. The National Committee for Clinical Laboratory Standards: 
Document EP5-T2, Evaluation of Precision Performance of Clinical 
Chemistry Devices; Document EP9-A, Method Comparison and Bias 
Estimation Using Patient Samples; Document EP7-P, Interference 
Testing in Clinical Chemistry.

List of Subjects in 21 CFR Part 866

    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 
866 is amended as follows:

PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES

    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.

    2. Section 866.6010 is revised to read as follows:

Sec. 866.6010  Tumor-associated antigen immunological test system.

    (a) Identification. A tumor-associated antigen immunological test 
system is a device that consists of reagents used to qualitatively or 
quantitatively measure, by immunochemical techniques, tumor-associated 
antigens in serum, plasma, urine, or other body fluids. This device is 
intended as an aid in monitoring patients for disease progress or 
response to therapy or for the detection of recurrent or residual 
disease.
    (b) Classification. Class II (special controls). Tumor markers must 
comply with the following special controls: (1) A guidance document 
entitled ``Guidance Document for the Submission of Tumor Associated 
Antigen Premarket Notifications (510(k)s) to FDA,'' and (2) voluntary 
assay performance standards issued by the National Committee on 
Clinical Laboratory Standards.

    Dated: November 6, 1997.
Joseph A. Levitt,
Deputy Director for Regulations Policy, Center for Devices and 
Radiological Health.
[FR Doc. 97-32876 Filed 12-16-97; 8:45 am]
BILLING CODE 4160-01-F