
[Federal Register Volume 76, Number 56 (Wednesday, March 23, 2011)]
[Rules and Regulations]
[Pages 16292-16294]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-6620]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2011-N-0026]


Medical Devices; Immunology and Microbiology Devices; 
Classification of Ovarian Adnexal Mass Assessment Score Test System

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is classifying the 
ovarian adnexal mass assessment score test system into class II 
(special controls). The special control that will apply to these 
devices is the guidance document entitled ``Guidance for Industry and 
FDA Staff; Class II Special Controls Guidance Document: Ovarian Adnexal 
Mass Assessment Score Test System.'' The Agency is classifying these 
devices into class II (special controls) because special controls, in 
addition to general controls, will provide a reasonable assurance of 
safety and effectiveness of these devices and there is sufficient 
information to establish special controls. Elsewhere in this issue of 
the Federal Register, FDA is announcing the availability of a guidance 
document that will serve as the special control for these devices.

DATES: Effective Date: April 22, 2011. The classification was effective 
September 11, 2009.

FOR FURTHER INFORMATION CONTACT: Donna Roscoe, Center for Devices and 
Radiological Health, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 66, rm. 5540, Silver Spring, MD 20993-0002, 301-796-6183.

SUPPLEMENTARY INFORMATION:

I. Legal Authority

    The Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 301 
et seq.), as amended by the Medical Device Amendments of 1976 (the 1976 
amendments) (Pub. L. 94-295), the Safe Medical Devices Act of 1990 (the 
SMDA) (Pub. L. 101-629), and the Food and Drug Administration 
Modernization Act (the FDAMA) (Pub. L. 107-250) established a 
comprehensive system for the regulation of medical devices intended for 
human use. Section 513 of the FD&C Act (21 U.S.C. 360c) established 
three categories (classes) of devices, depending on the regulatory 
controls needed to provide reasonable assurance of their safety and 
effectiveness. The three categories of devices are class I (general 
controls), class II (special controls), and class III (premarket 
approval).
    FDA refers to devices that were not in commercial distribution 
before May 28, 1976 (the date of enactment of the 1976 amendments), as 
postamendments devices. Postamendments devices are classified 
automatically by statute (section 513(f) of the FD&C Act into class III 
without any FDA rulemaking process. These devices remain in class III 
and require premarket approval, unless: (1) FDA reclassifies the device 
into class I or II; (2) FDA issues an order classifying the device into 
class I or class II in accordance with section 513(f)(2) of the FD&C 
Act; or (3) FDA issues an order finding the device to be substantially 
equivalent, under section 513(i), 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 FD&C Act (21 U.S.C. 
360(k)) and part 807 of the regulations (21 CFR part 807).
    A person may market a preamendments device that has been classified 
into class III through premarket notification procedures, without 
submission of a premarket approval application (PMA) until FDA issues a 
final regulation under section 515(b) of the FD&C Act (21 U.S.C. 
360e(b)) requiring premarket approval.
    Reclassification of postamendments devices is governed by section 
513(f)(3) of the FD&C Act, formerly section 513(f)(2). This section 
provides that FDA may initiate the reclassification of a device 
classified into class III under section 513(f)(1) of the FD&C Act, or 
the manufacturer or importer of a device may petition the Secretary for 
the issuance of an order classifying the device in class I or class II. 
FDA's regulations in 21 CFR 860.134 set forth the procedures for the 
filing and review of a petition for reclassification of such class III 
devices. In order to change the classification of the device, it is 
necessary that the proposed new class have sufficient regulatory 
controls to provide reasonable assurance of the safety and 
effectiveness of the device for its intended use.
    FDAMA added section 513(f)(2) to the FD&C Act which addresses 
classification of postamendments devices. Section 513(f)(2) of the FD&C 
Act provides that, upon receipt of a ``not substantially equivalent'' 
determination, a 510(k) applicant may request FDA to classify a 
postamendments device into class I or class II. Within 60 days from the 
date of such a written request, FDA must classify the device by written 
order. If FDA classifies the device into class I or II, the applicant 
has then received clearance to market the device and it can be used as 
a predicate device for other 510(k)s. It is expected that this process 
will be used for low risk devices. This process does not apply to 
devices that have been classified by regulation into class III--i.e., 
preamendments class III devices, or class III devices for which a PMA 
is appropriate.

II. Classification

    In accordance with section 513(f)(1) of the FD&C Act, FDA issued an 
order on July 16, 2009, classifying the Vermillion, Inc. OVA1\TM\ Test 
into 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 July 
22, 2009, Vermillion, Inc., submitted a petition requesting 
classification of the OVA1\TM\ Test under section 513(f)(2) of the FD&C 
Act. The manufacturer recommended that the device be classified into 
class II (Ref. 1).
    In accordance with section 513(f)(2) of the FD&C Act, FDA reviewed 
the petition in order to classify the device under the criteria for 
classification set forth in section 513(a)(1). FDA classifies devices 
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, the FDA determined that the device can be classified into 
class II with the establishment of special controls. FDA believes these 
special controls will provide reasonable assurance of the safety and 
effectiveness of the device.
    The device is assigned the generic name ovarian adnexal mass 
assessment score test system, and it is identified as a device that 
measures one or more proteins in serum or plasma. It yields a single 
result for the likelihood that an adnexal pelvic mass in a woman, for 
whom surgery is planned, is malignant. The test is for adjunctive use, 
in the context of a negative primary clinical and radiological 
evaluation, to augment the identification of patients whose gynecologic 
surgery requires oncology expertise and resources.

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III. Risks to Health

    FDA has identified the risks to health associated with this type of 
device as a false negative result, a false positive result, and off-
label use as a screening test, stand-alone diagnostic test, or as a 
test to determine whether or not to proceed with surgery. Failure of 
the system to perform as indicated could lead to inaccurate risk 
assessment and improper management of patients with ovarian 
malignancies. Specifically, a falsely low ovarian adnexal mass score 
could result in a determination that the patient may not have ovarian 
malignancy, which could lead to less than optimal surgical expertise 
and resources. A falsely high ovarian adnexal mass score could result 
in a determination that the patient may have ovarian malignancy which 
could lead to inappropriate surgical decisions and unnecessary patient 
anxiety. Off-label use of the test, including use of test results as a 
stand-alone diagnostic without consideration of other diagnostic 
testing and clinical assessment, could also pose a risk for morbidity 
and mortality due to non-referral for oncologic evaluation and 
treatment.
    FDA believes that the special controls guidance document, in 
addition to general controls, addresses the risks to health identified 
above and provides reasonable assurance of the safety and effectiveness 
of the device. Therefore, on September 11, 2009, FDA issued an order to 
the petitioner classifying the device into class II. FDA is codifying 
this device by adding Sec.  866.6050.

IV. 510(k) Premarket Notification

    Following the effective date of this final classification rule, any 
firm submitting a 510(k) premarket notification for ovarian adnexal 
mass assessment score 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 FD&C 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, FDA has determined because of the 
risks of false positives and negatives and off label use that premarket 
notification is necessary to provide 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 ovarian adnexal mass assessment score test system they intend 
to market.

V. 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.

VI. 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 (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 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 this rule is deregulatory and imposes no new 
burdens, 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 $135 million, using the most current (2009) 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.

A. Background

    An ovarian adnexal mass assessment test system is a device that 
measures one or more proteins in serum or plasma to yield a single 
result for the likelihood that an adnexal pelvic mass in a woman for 
whom surgery is planned is malignant. Such a test would identify women 
who would benefit from referral to a gynecological oncologist, despite 
negative results from other clinical and radiographic tests for ovarian 
cancer.
    The ovarian adnexal mass assessment test system device is currently 
classified into class III, the highest level of regulatory oversight. 
The device was initially placed in this classification automatically 
because there was no predicate device to which it could be found 
substantially equivalent. Manufacturers of ovarian adnexal mass 
assessment test systems, as makers of class III devices, bear all costs 
associated with premarket approval, including the cost of submitting 
the premarket approval application (PMA) and payment of user fees. The 
costs associated with the submission of the PMA are substantial, 
potentially reaching $1,000,000.
    We are aware of a single manufacturer producing a single product 
affected by this device classification. The manufacturer submitted a 
request for Evaluation of Automatic Class III Designation, recommending 
classification into class II. Placing this device in a classification 
with less burdensome regulatory requirements affects the current 
manufacturer and potentially affects others, encouraging future entry 
into this market.
    In response to the manufacturer request, FDA is classifying ovarian 
adnexal mass assessment test system devices into class II. Based on the 
experience of FDA reviewers, the Agency concludes that the ovarian 
adnexal mass assessment test system device would not be safe and 
effective under general controls. FDA has therefore chosen special 
controls to address the specific risks of false positives, false 
negatives, and off-label use. These special controls in addition to the 
application of general controls would be consistent with the principle 
of applying the least degree of regulatory control necessary to provide 
reasonable assurance of safety and effectiveness. The application of 
this intermediate level of regulatory oversight would be consistent 
with the treatment of other devices with similar risk profiles.
    The special controls recommend a black box warning to reduce the 
risks of off-label use. The Agency is separately

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proposing to require the application of the black box warning to 
labeling and advertising through notice and comment rulemaking. For the 
purposes of this analysis, we assume that this final rule will 
establish special controls with a reference to a black box warning 
regarding off-label use, but the analysis of the impact of the addition 
of the warning to the product label will be included in a separate 
rulemaking.

B. Costs of the Final Rule

    This final rule is deregulatory. Device manufacturers currently 
subject to class III requirements will be subject to the less 
burdensome requirements for makers of class II devices. Through this 
classification, manufacturers of ovarian adnexal mass assessment test 
system devices will be relieved of the obligation to submit a PMA prior 
to marketing. The cost of submitting a PMA can reach $1,000,000, plus 
user fees of an additional $217,787 in FY 2010, increasing to $256,384 
in 2012. This device classification will substantially reduce an 
existing burden on manufacturers of ovarian adnexal mass assessment 
test system devices. Considering the cost of submitting a PMA plus the 
relevant user fees, the reduction could be $1,000,000 per device.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Classification of the affected device into class II 
after it had automatically been placed in class III will relieve 
manufacturers of the cost of complying with the premarket approval 
requirements of section 515 of the FD&C Act. Because of the reduced 
burden, the Agency does not believe that this final rule will have a 
significant economic impact on a substantial number of small entities.

VII. 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 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, 
Inc., 552 U.S. 312 (2008). The special controls established by this 
rulemaking create ``requirements'' to address each identified risk to 
health presented by these specific medical devices under 21 U.S.C. 
360k, even though product sponsors may have flexibility in how they 
meet those requirements. Cf. Papike v. Tambrands, Inc., 107 F.3d 737, 
740-42 (9th Cir. 1997).

VIII. 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 Budget under the Paperwork 
Reduction Act of 1995 (44 U.S.C. 3501-3520). Elsewhere in this issue of 
the Federal Register, FDA is publishing a notice announcing the 
availability of the guidance document entitled ``Guidance for Industry 
and FDA Staff; Class II Special Controls Guidance Document: Ovarian 
Adnexal Mass Assessment Score Test System.'' The notice contains an 
analysis of the paperwork burden for the guidance.

IX. References

    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 Vermillion, Inc., for reclassification of the 
OVA1\TM\ Test submitted July 22, 2009.

List of Subjects in 21 CFR Part 866

    Biologics, Laboratories, 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

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 866.6050 is added to subpart G to read as follows:


Sec.  866.6050  Ovarian adnexal mass assessment score test system.

    (a) Identification. An ovarian/adnexal mass assessment test system 
is a device that measures one or more proteins in serum or plasma. It 
yields a single result for the likelihood that an adnexal pelvic mass 
in a woman, for whom surgery is planned, is malignant. The test is for 
adjunctive use, in the context of a negative primary clinical and 
radiological evaluation, to augment the identification of patients 
whose gynecologic surgery requires oncology expertise and resources.
    (b) Classification. Class II (special controls). The special 
control for this device is FDA's guidance document entitled ``Class II 
Special Controls Guidance Document: Ovarian Adnexal Mass Assessment 
Score Test System.'' For the availability of this guidance document, 
see Sec.  866.1(e).

    Dated: March 16, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-6620 Filed 3-22-11; 8:45 am]
BILLING CODE 4160-01-P


