Document ID: FDA-2011-N-0029-0001
Agency: fda
Document Type: Proposed Rule
Title: Medical Devices Ovarian Adnexal Mass Assessment Score Test System; Labeling; Black Box Restrictions
Posted Date: 2011-03-23T04:00Z

[Federal Register Volume 76, Number 56 (Wednesday, March 23, 2011)]
[Proposed Rules]
[Pages 16350-16353]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-6621]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2010-N-0029]

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

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
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. Elsewhere in this issue of the 
Federal Register, FDA is announcing a final rule that classifies the 
ovarian adnexal mass assessment score test system into class II 
(special controls).

DATES: Submit either electronic or written comments by May 23, 2011.

ADDRESSES: You may submit comments, identified by Docket No. FDA-2010-
N-0029, by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     Fax: 301-827-6870.
     Mail/Hand delivery/Courier (for paper, disk, or CD-ROM 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name 
and Docket No. FDA-2010-N-0029. All comments received may be posted 
without change to http://www.regulations.gov, including any personal 
information provided. For additional information on submitting 
comments, see the ``Comments'' heading of the SUPPLEMENTARY INFORMATION 
section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number, found in brackets in the heading of this document, into 
the ``Search'' box and follow the prompts and/or go to the Division of 
Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

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 proposed rule?

A. Ovarian Adnexal Mass Assessment Score Test System

    An ovarian adnexal mass assessment score test system measures one 
or more analytes in serum and combines the values into a single score 
that is then used to determine the likelihood that the pre-surgical 
adnexal mass in a woman not yet referred to an oncologist, is 
malignant. An ovarian adnexal mass assessment score test system is 
intended for use in those patients for whom surgery is planned, and 
should not be used to decide whether or not a patient should receive 
surgery. The test is used in conjunction with a clinical and 
radiological evaluation of the patient by physicians in determining 
whether the patient should be referred to a gynecologic oncologist for 
surgery.

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

[[Page 16351]]

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 proposing to require 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. While FDA is establishing as a special control ``Guidance 
for Industry and FDA Staff; Class II Special Controls Guidance 
Document: Ovarian Adnexal Mass Assessment Score Test System'' which 
recommends a black box warning to address the risk of off-label use, 
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)). A 
notice of availability of this special controls guidance document is 
published elsewhere in this issue of the Federal Register.
    In cases in which class II and class III devices have significant 
risks that would make the devices unsafe if used inappropriately, FDA 
believes the risks need to 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 proposed prominent black box warning would read as follows:
[GRAPHIC] [TIFF OMITTED] TP23MR11.000

III. What is the legal authority for this proposed rule?

    FDA is issuing this proposed 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 proposed 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)).

IV. What is the environmental impact of this proposed 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.

V. What is the economic impact of this proposed rule?

    FDA has examined the impacts of the proposed 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 proposed rule is not a significant regulatory action as defined by 
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 proposed rule would strengthen existing 
cautions against misuse of a new product, the Agency proposes to 
certify 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 
proposed 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

[[Page 16352]]

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 proposed rule under section 520(e) of the FD&C Act. 
Through this action, the Agency proposes to require a black box warning 
on product labeling, advertising, and promotional materials for ovarian 
adnexal mass assessment test systems. This warning would make users 
aware of the limitations of this device and the serious risks 
associated with its misuse. With the proposed addition of this black 
box warning to product labeling, advertising, and marketing materials, 
the Agency concludes there would be a reasonable assurance of the 
safety and effectiveness of ovarian adnexal mass assessment test 
systems.
    The economic impact of this proposed rule is expected to be very 
small. We are aware of a single manufacturer producing a single product 
that would 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 proposal 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 significant impact of a rule 
on small entities. This proposal would impose almost no cost on 
manufacturers. The proposed black box warning would strengthen an 
existing admonition against off-label use and would not significantly 
affect usage. Impacts on any entities would be so small as to be 
difficult to quantify. For these reasons, the Agency proposes to 
certify that this rule would not have a significant economic impact on 
a substantial number of small entities.

VI. How does the Paperwork Reduction Act of 1995 apply to this proposed 
rule?

    FDA concludes that labeling provisions of this proposed 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)).

VII. What are the federalism impacts of this proposed rule?

    FDA has analyzed this proposed 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, Inc., 552 U.S. 312 (2008)). If this proposed rule is made 
final, the final rule would create 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.

VIII. How do you submit comments on this proposed rule?

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) either electronic or written comments regarding this 
document. It is only necessary to send one set of comments. It is no 
longer necessary to send two copies of mailed comments. Identify 
comments with the docket number found in brackets in the heading of 
this document. Received comments may be seen in the Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday.

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 proposes 
to amend 21 CFR part 866 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. 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:

[[Page 16353]]

[GRAPHIC] [TIFF OMITTED] TP23MR11.001

    Dated: March 16, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-6621 Filed 3-22-11; 8:45 am]
BILLING CODE 4160-01-P