Final Rule: Medical Devices; Ovarian Adnexal Mass Assessment Score Test 
System; Labeling; Black Box Restrictions

Federal Register: Volume 76, Number 251 (Friday, December 30, 2011)
                  Pages 82129-82131

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug Administration (FDA) is amending the 
regulation classifying ovarian adnexal mass assessment score test 
systems to restrict these devices so that a prescribed warning 
statement that addresses a risk identified in the special controls 
guidance document must be in a black box and must appear in all 
labeling, advertising, and promotional material. The black box warning 
mitigates the risk to health associated with off-label use as a 
screening test, stand-alone diagnostic test, or as a test to determine 
whether or not to proceed with surgery.

DATES: Effective Date: January 30, 2012.

FOR FURTHER INFORMATION CONTACT: Scott McFarland, Center for Devices 
and Radiological Health, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 66, Rm. 5543, Silver Spring, MD 20993-0002, (301) 
796-6217.

SUPPLEMENTARY INFORMATION:

I. What is the background of this final rule?

A. Ovarian Adnexal Mass Assessment Score Test System

    An ovarian adnexal mass assessment score 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. Identified Risk to Health

    The ovarian adnexal mass assessment score test system is not 
indicated for use as a screening or diagnostic test for ovarian cancer. 
Off-label use of the test (e.g., in patients who are not already 
identified as needing surgery for pelvic mass or without reference to 
an independent clinical/radiological evaluation of the patient), may 
lead to a high frequency of unnecessary further testing and surgery due 
to false positive results, or to delay in tumor diagnosis due to false 
negative results.

II. Why is FDA requiring black box warnings on ovarian adnexal mass 
assessment score test system labeling, advertising, and promotional 
material?

    FDA has determined that in order to provide reasonable assurance of 
safety and effectiveness, it is necessary to restrict the ovarian 
adnexal mass assessment score test system to sale, distribution, and 
use with labeling, advertising, and promotional material that bears a 
warning statement in a black box that alerts users to the risk 
associated with off-label use as a screening test, stand-alone 
diagnostic test, or as a test to determine whether or not to proceed 
with surgery. In the Federal Register of March 23, 2011 (76 FR 16292 at 
12694), FDA published a final rule that classified this device into 
class II and established as a special control the guidance entitled 
``Class II Special Controls Guidance Document: Ovarian Adnexal Mass 
Assessment Score Test System'' that recommends a black box warning to 
address the risk of off-label use. In the Federal Register of March 23, 
2011 (76 FR 16425), FDA published a notice of availability of this 
special controls guidance document. However, FDA believes it is 
necessary to require this warning in labeling and advertising by 
restricting the device under section 520(e) of the Federal Food, Drug, 
and Cosmetic Act (FD&C Act) (21 U.S.C. 360j(e)). In the Federal 
Register of March 23, 2011 (76 FR 16350 at 16352), FDA published a 
proposed rule to require the black box warning.
    For devices that have significant risks that would make the devices 
unsafe if used inappropriately, FDA may require that the risks be 
explained in warning statements placed in a black box that is displayed 
prominently in the labeling, advertising, and promotional material to 
ensure awareness by the end user. Awareness of these important risks by 
the end user enables these devices to be used safely. In this case, a 
prominent black box warning, which alerts the user to the limitations 
of this device, is necessary in all labeling, advertising, and 
promotional materials to allow ovarian adnexal mass assessment score 
test system devices to be used safely. The prominent black box warning 
must read as follows:

[[Page 82130]]

[GRAPHIC] [TIFF OMITTED] TR30DE11.007

III. What comments did FDA receive on this rule?

    In the Federal Register of March 23, 2011 (76 FR 16350 at 16352), 
FDA announced the proposed rule to require the black box warning. 
Comments on the proposed rule were due by May 23, 2011. FDA received 
one comment in the docket for the proposed rule from a consumer. The 
comment supported the proposed rule.

IV. What is the legal authority for this final rule?

    FDA is issuing this final rule under the authority of section 
520(e) of the FD&C Act, which authorizes FDA to restrict sale, 
distribution, and use of devices upon certain conditions. FDA is also 
issuing this final rule under general device and administrative 
provisions of the FD&C Act (sections 501, 510, 513, 515, 520, and 701 
(21 U.S.C. 351, 360, 360c, 360e, 360j, and 371, respectively)).

V. What is the environmental impact of this final rule?

    FDA has determined under 21 CFR 25.34(b) and (f) 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. What is the economic impact of this final rule?

    FDA has examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct 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 Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because this final rule strengthens existing 
cautions against misuse of a product, 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 $136 million, using the most current (2010) 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.
    An ovarian adnexal mass assessment test system is a device that 
measures one or more proteins in serum to yield a single result for the 
likelihood that an adnexal pelvic mass in a woman is malignant. Such a 
test would identify women whose planned gynecologic surgery would 
benefit from referral to a gynecological oncologist, despite negative 
results from other clinical and radiographic tests for ovarian cancer.
    In considering the appropriate level of regulatory oversight for 
this device, FDA concluded in classifying the device that general and 
special controls to minimize the risk of false positive and false 
negative results, and risks associated with improper off-label use 
would provide a reasonable assurance of safety and effectiveness of the 
ovarian adnexal mass assessment test system. The special controls 
guidance recommends use of a black box warning to minimize these risks. 
Without such a strong warning, ovarian adnexal mass assessment test 
systems might be used as a screening test, stand-alone diagnostic test, 
or as a test to determine whether or not to proceed with surgery. Off-
label use of the test or the use of test results without consideration 
of other diagnostic testing and clinical assessment could pose a risk 
for morbidity and mortality due to nonreferral for oncologic evaluation 
and treatment.
    In order to require the specific black box warning on labeling and 
on all advertising and promotional materials for the device, FDA is 
issuing this final rule under section 520(e) of the FD&C Act. Through 
this action, the Agency requires a black box warning on product 
labeling, advertising, and promotional materials for ovarian adnexal 
mass assessment test systems. This warning will make users aware of the 
limitations of this device and the serious risks associated with its 
misuse. With the addition of this black box warning to product 
labeling, advertising, and marketing materials, the Agency concludes 
there will be a reasonable assurance of the safety and effectiveness of 
ovarian adnexal mass assessment test systems.
    The economic impact of this final rule is expected to be very 
small. We are aware of a single manufacturer producing a single product 
that will be affected by this black box warning. The manufacturer 
should be able to incorporate the warning in the course of developing 
its product labeling. The admonition against off-label use for this 
device already exists, so the addition of this type of warning is not 
expected to have a significant effect on the market for this product. 
The expected impact of this final rule on the market for this product 
would be a reduction in off-label use among the small number of users 
who would be undeterred by a less visible warning.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any

[[Page 82131]]

significant impact of a rule on small entities. This final rule would 
impose almost no cost on manufacturers. The black box warning will 
strengthen an existing admonition against off-label use and will not 
significantly affect usage. Impacts on any entities will be so small as 
to be difficult to quantify. For these reasons, the Agency certifies 
that this rule will not have a significant economic impact on a 
substantial number of small entities.

VII. How does the Paperwork Reduction Act of 1995 apply to this final 
rule?

    FDA concludes that labeling provisions of this final rule are not 
subject to review by the Office of Management and Budget because they 
do not constitute a ``collection of information'' under the Paperwork 
Reduction Act of 1995 (44 U.S.C. 3501-3520). Rather, the black box 
warning on all labeling, advertising, and promotional materials for 
ovarian adnexal mass assessment score test system devices is a ``public 
disclosure of information originally supplied by the Federal Government 
to the recipient for the purpose of disclosure to the public.'' (see 5 
CFR 1320.3(c)(2)).

VIII. What are the federalism impacts of this final rule?

    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, Inc. v. Lohr, 518 U.S. 470 (1996); Riegel 
v. Medtronic, Inc., 552 U.S. 312 (2008)). This final rule creates a 
requirement under 21 U.S.C. 360k for a black box warning statement that 
must appear in all advertising, labeling, and promotional material for 
ovarian adnexal mass assessment score test systems.

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, FDA amends 
21 CFR part 866 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. In Sec.  866.6050 of subpart G, add new paragraph (c) to read as 
follows:


Sec.  866.6050  Ovarian adnexal mass assessment score test system.

* * * * *
    (c) Black box warning. Under section 520(e) of the Federal Food, 
Drug, and Cosmetic Act these devices are subject to the following 
restriction: A warning statement must be placed in a black box and must 
appear in all advertising, labeling, and promotional material for these 
devices. That warning statement must read:
[GRAPHIC] [TIFF OMITTED] TR30DE11.007


    Dated: December 27, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-33588 Filed 12-29-11; 8:45 am]
BILLING CODE 4160-01-P