**Draft Guidance for**

**Industry and FDA Staff**

**Class II Special Controls Guidance Document: Bone Sonometers**

***Draft Guidance***

**This guidance document is being distributed for comment purposes
only.** []{.mark}

**Document issued on: \[***OSM will insert release date of FR Notice on
posting***\]**

Comments and suggestions regarding this draft document should be
submitted within 90 days of publication in the *Federal Register* of the
notice announcing the availability of the draft guidance. Submit written
comments to the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
Alternatively, electronic comments may be submitted to
<http://www.fda.gov/dockets/ecomments>. All comments should be
identified with the docket number listed in the notice of availability
that publishes in the *Federal Register*.

For questions regarding this document contact Robert A. Phillips,
301-594-1212, ext. 130.

**When final this document will supersede Bone Sonometer PMA
Applications; Final Guidance for Industry and FDA, issued June 21,
2001.**

![](media/image1.png)

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Devices and Radiological Health**

**Radiological Devices Branch\
Division of Reproductive, Abdominal, and Radiological Devices**

**Office of Device Evaluation**

**Preface**

**Additional Copies**

Additional copies are available from the Internet at:
[[http://www.fda.gov/cdrh/\[specific]{.underline}](http://www.fda.gov/cdrh/%5Bspecific)
address\], or to receive this document via your fax machine, call the
CDRH Facts-On-Demand system at 800-899-0381 or 301-827-0111 from a
touch-tone telephone. Press 1 to enter the system. At the second voice
prompt, press 1 to order a document. Enter the document number
(**1547**) followed by the pound sign (#). Follow the remaining voice
prompts to complete your request.

> **Table of Contents**

[1. Introduction 1](#introduction)

[2. Background 2](#background)

[3. The Content and Format of an Abbreviated 510(k) Submission
2](#the-content-and-format-of-an-abbreviated-510k-submission)

[4. Scope 5](#scope)

[5. Device Description 6](#device-description)

[6. Risks to Health 7](#risks-to-health)

[7. Electrical Safety 8](#electrical-safety)

[8. Electromagnetic Compatibility 8](#electromagnetic-compatibility)

[9. Acoustic Intensity 9](#acoustic-intensity)

[10. Non-Clinical Testing 9](#non-clinical-testing)

[11. Clinical Testing 10](#clinical-testing)

[12. Labeling 14](#labeling)

**Draft Guidance for Industry and FDA Staff**

**Class II Special Controls Guidance Document: Bone Sonometers**

***This draft guidance, when finalized, will represent the Food and Drug
Administration\'s (FDA\'s) current thinking on this topic. It does not
create or confer any rights for or on any person and does not operate to
bind FDA or the public. You can use an alternative approach if the
approach satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative approach, contact the
FDA staff responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number listed
on the title page of this guidance.***

# Introduction

This draft guidance document was developed as a special controls
guidance to support the reclassification of bone sonometers into class
II (special controls). The device transmits ultrasound energy into the
human body to measure the acoustic properties of bone that indicate
overall bone health and fracture risk.

This draft guidance will be issued in conjunction with a Federal
Register notice announcing the proposal to reclassify this device type.
This guidance is issued for comment purposes only. If a final rule to
reclassify this device type is not issued, this guidance document will
not be issued as a special control.

Following the effective date of a final rule reclassifying the device,
any firm submitting a premarket notification submission (510(k)) for a
bone sonometer will need to address the issues covered in the special
control guidance. However, the firm need only show that its device meets
the recommendations of the guidance or in some other way provides
equivalent assurances of safety and effectiveness.

When final this document will supersede the guidance entitled, **Bone
Sonometer PMA Applications**, issued June 21, 2001
(<http://www.fda.gov/cdrh/ode/guidance/1377.html>).

> **The Least Burdensome Approach**
>
> This draft guidance document reflects our careful review of what we
> believe are the relevant issues related to bone sonometers and what we
> believe would be the least burdensome way of addressing these issues.
> If you have comments on whether there is a less burdensome approach,
> however, please submit your comments as indicated on the cover of this
> document.

FDA\'s guidance documents, including this guidance, do not establish
legally enforceable responsibilities. Instead, guidances describe the
Agency\'s current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements
are cited. The use of the word *should* in Agency guidances means that
something is suggested or recommended, but not required.

# Background

> FDA believes that special controls, when combined with the general
> controls, will be sufficient to provide reasonable assurance of the
> safety and effectiveness of bone sonometers. Thus, a manufacturer who
> intends to market a device of this generic type should (1) conform to
> the general controls of the Federal Food, Drug, and Cosmetic Act (the
> act), including the premarket notification requirements described in
> 21 CFR 807 Subpart E, (2) address the specific risks to health
> associated with bone sonometers identified in this guidance, and (3)
> obtain a substantial equivalence determination from FDA prior to
> marketing the device.

This special control guidance document identifies the classification
regulation and product code for the bone sonometer (Please refer to
**Section 4.** **Scope)**. In addition, other sections of this special
control guidance document list the risks to health identified by FDA and
describe measures that, if followed by manufacturers and combined with
the general controls, will generally address the risks associated with
these bone sonometers and lead to a timely 510(k) review. This document
supplements other FDA documents regarding the specific content
requirements of a premarket notification submission. You should also
refer to 21 CFR 807.87 and "**How to Prepare a 510(k) Submission**" on
FDA's Device Advice at <http://www.fda.gov/cdrh/devadvice/314.html>.

As described in the guidance entitled, **The New 510(k) Paradigm -
Alternate Approaches to Demonstrating Substantial Equivalence in
Premarket Notifications; Final Guidance**,
<http://www.fda.gov/cdrh/ode/parad510.html>, a manufacturer may submit a
Traditional 510(k) or has the option of submitting either an Abbreviated
510(k) or a Special 510(k). FDA believes an Abbreviated 510(k) provides
the least burdensome means of demonstrating substantial equivalence for
a new device, particularly once FDA issues a class II special controls
guidance document. Manufacturers considering certain modifications to
their own cleared devices may lessen the regulatory burden by submitting
a Special 510(k).

# The Content and Format of an Abbreviated 510(k) Submission 

An Abbreviated 510(k) submission must include the required elements
identified in 21 CFR 807.87, including the proposed labeling for the
device sufficient to describe the device, its intended use, and the
directions for its use. In an Abbreviated 510(k), FDA may consider the
contents of a summary report to be appropriate supporting data within
the meaning of 21 CFR 807.87(f) or (g); therefore, we recommend that you
include a summary report. The report should describe how this special
control guidance document was used during the device development and
testing and should briefly describe the methods or tests used and a
summary of the test data or description of the acceptance criteria
applied to address the risks identified in this document, as well as any
additional risks specific to your device. This section suggests
information to fulfill some of the requirements of section 807.87 as
well as some other items that we recommend you include in an Abbreviated
510(k).

> **Coversheet**
>
> The coversheet should prominently identify the submission as an
> Abbreviated 510(k) and cite the title of this special controls
> guidance document.
>
> **Proposed labeling**
>
> Proposed labeling should be sufficient to describe the device, its
> intended use, and the directions for its use. (Please refer to
> **Section 11.** **Labeling** for specific information that should be
> included in the labeling for devices of the type covered by this
> guidance document.)
>
> **Summary report**

We recommend that the summary report contain:

> **Description of the device and its intended use**
>
> We recommend that you describe the performance specifications and,
> when appropriate, include detailed, labeled drawings of the device.
> (Please refer to **Section 5**. **Device Description** for specific
> information that we recommend you include in the device description
> for devices of the type covered by this guidance document.) You should
> also submit an "indications for use" enclosure.[^1]
>
> **Description of device design requirements**
>
> We recommend that you include a brief description of the device design
> requirements.
>
> **Identification of the risk analysis method**
>
> We recommend that you identify the risk analysis method(s) you used to
> assess the risk profile, in general, as well as the specific device's
> design and the results of this analysis. (Please refer to **Section 6.
> Risks to Health** for the risks to health generally associated with
> the use of this device that FDA has identified.)
>
> **Discussion of the device characteristics**
>
> We recommend that you discuss the device characteristics that address
> the risks identified in this class II special controls guidance
> document, as well as any additional risks identified in your risk
> analysis.
>
> **Description of the performance aspects**
>
> We recommend that you include a brief description of the test
> method(s) you have used or intend to use to address each performance
> aspect identified in **Sections 7 - 10** of this class II special
> controls guidance document. If you follow a suggested test method, you
> may cite the method rather than describing it. If you modify a
> suggested test method, you may cite the method but should provide
> sufficient information to explain the nature of and reason for the
> modification. For each test, you may either (1) briefly present the
> data resulting from the test in clear and concise form, such as a
> table, **[or]{.underline}** (2) describe the acceptance criteria that
> you will apply to your test results.[^2] (See also 21 CFR 820.30,
> Subpart C - Design Controls for the Quality System Regulation.)
>
> **Reliance on standards**
>
> If any part of the device design or testing relies on a recognized
> standard, we recommend that you include either:

-   a statement that testing will be conducted and meet specified
    acceptance criteria before the device is marketed or

-   a declaration of conformity to the standard.[^3]

> Because a declaration of conformity is based on results from testing,
> we believe you cannot properly submit a declaration of conformity
> until you have completed the testing the standard describes. For more
> information, please refer to section 514(c)(1)(B) of the Act and the
> FDA guidance, **Use of Standards in Substantial Equivalence
> Determinations; Final Guidance for Industry and
> FDA**.<http://www.fda.gov/cdrh/ode/guidance/1131.html>.

If it is not clear how you have addressed the risks identified by FDA or
additional risks identified through your risk analysis, we may request
additional information about aspects of the device's performance
characteristics. We may also request additional information if we need
it to assess the adequacy of your acceptance criteria. (Under 21 CFR
807.87(l), we may request any additional information that is necessary
to reach a determination regarding substantial equivalence.)

As an alternative to submitting an Abbreviated 510(k), you can submit a
Traditional 510(k) that provides all of the information and data
required under 21 CFR 807.87 and described in this guidance. A
Traditional 510(k) should include all of your methods, data, acceptance
criteria, and conclusions. Manufacturers considering certain
modifications to their own cleared devices should consider submitting
Special 510(k)s.

The general discussion above applies to any device subject to a special
controls guidance document. The following is a specific discussion of
how you should apply this special controls guidance document to a
premarket notification submission for a bone sonometer.

# Scope

The scope of this document is limited to the device described below[^4].

> 21 CFR 892.1180, class II \[product code to be designated, if a final
> rule is published\].
>
> A bone sonometer is a device that transmits ultrasound energy into the
> human body to measure acoustic properties of bone that indicate
> overall bone health and fracture risk. The primary components of the
> device are a voltage generator, a transmitting transducer, a receiving
> transducer, and hardware and software for reception and processing of
> the received ultrasonic signal.

This guidance addresses the following indications:

-   determining the possible presence of osteoporosis and assessing
    fracture risk

-   monitoring bone changes over time

-   assessing non-age-related bone loss.

# Device Description 

We recommend that you identify your device, by the regulation and
product code described in section **4. Scope,** and provide the
information discussed below.

**Sonometer**

We recommend that you provide a complete description of the device,
including:

-   indications for use

-   physical description of the device, including how transducers are
    positioned on the body and anatomical site(s) scanned

-   engineering or block diagrams showing the major components

-   block diagram of the data analysis program

-   calibration standards used (built-in and external).

    **Hardware**

    We recommend that you provide the following specifications:

-   transducer diameter, resonant frequency, bandwidth, focusing
    properties

-   A/D converter sampling rate and bit depth.

    **Software**

> We recommend that you include the appropriate software documentation
> as described in the guidance titled, **Guidance for the Content of
> Premarket Submissions for Software Contained in Medical Devices** at
> [www.fda.gov/cdrh/ode/guidance/337.html](http://www.fda.gov/cdrh/ode/guidance/337.html).
> As discussed in that guidance, we recommend that you identify the
> "level of concern" (minor, moderate, or major) associated with your
> device and provide documentation consistent with that level.
> Generally, we consider "minor level of concern" appropriate for the
> bone sonometers addressed in this class II special controls guidance
> document.

**Beam**

We recommend that you describe the beam (e.g., size, spectra,
intensity). The description should include the average and maximum
acoustic intensities measured for the device (e.g., I~SPPA.3~,
I~SPTA.3~, MI). See also the guidance entitled, **Information for
Manufacturers Seeking Marketing Clearance of Diagnostic Ultrasound
Systems and Transducers**, at <http://www.fda.gov/cdrh/ode/ulstran.pdf>.

[]{.mark}

**Phantoms**

> If the device uses phantoms, for example in quality control or
> maintenance procedures, we recommend that you discuss the design,
> including contents, of any phantoms used. We also recommend that you
> provide a product sheet detailing the technical and descriptive
> specifications of the phantom(s) and explain how the phantoms are
> used.

**Accessories**

> We recommend that you list all accessories that you intend to make
> available for use with your bone sonometer. In addition, for each of
> your accessories, we recommend that you provide:

-   a complete description, including photographs or drawings, and
    construction, including materials

-   any material standards met

-   any previous clearance.

> If an accessory is exempt from the 510(k) requirements of the act, we
> recommend that you indicate its classification regulation. If your
> accessory is not exempt or previously cleared for this use, bundling
> with your bone sonometer submission may be appropriate. For
> information about bundling premarket submissions see the guidance
> entitled, **Bundling Multiple Devices or Multiple Indications in a
> Single Submission**.[^5]

# Risks to Health 

In the table below, FDA has identified the risks to health generally
associated with the use of the device addressed in this document. The
measures recommended to mitigate these identified risks are given in
this guidance document, as shown in the table below. We recommend that
you also conduct a risk analysis, befeore submitting your 510(k), to
identify any other risks specific to your device and include the results
of this analysis in your 510(k). If you elect to use an alternative
approach to address a particular risk identified in this document, or
have identified risks additional to those in this document, then you
should provide sufficient detail to support the approach you have used
to address that risk.

+--------------------------------------+-------------------------------+
| ### **Identified r                   | **Recommended mitigation      |
| isk** {#identified-risk .unnumbered} | measures (see guidance        |
|                                      | section below)**              |
+--------------------------------------+-------------------------------+
| Electrical shock                     | > 7\. Electrical Safety       |
+--------------------------------------+-------------------------------+
| Electromagnetic interference         | > 8\. Electromagnetic         |
|                                      | > compatibility               |
+--------------------------------------+-------------------------------+
| Tissue damage                        | > 9\. Acoustic Intensity      |
+--------------------------------------+-------------------------------+
| Inaccurate measurement leading to    | > 10\. Non-Clinical Testing   |
| inappropriate diagnosis or therapy   | >                             |
|                                      | > 11\. Clinical Testing       |
|                                      | >                             |
|                                      | > 12\. Labeling               |
+--------------------------------------+-------------------------------+

# Electrical Safety

We recommend that you evaluate the electrical safety of your device and
its ability to function after exposure to environmental handling
hazards. We recommend that you evaluate your device according to **[one
or more]{.underline}** of the following standards (or equivalent
methods):

-   International Electrotechnical Commission (IEC) 60601-1 Medical
    Electrical Equipment - Part 1: General Requirements for Safety

-   Underwriters Laboratory (UL) 2601-1 Amendment 1 Medical Electrical
    Equipment: General Requirements for Safety

-   American National Standards Institute (ANSI)/AAMI ES-1 Safe current
    limits for electromedical apparatus

-   IEC 60529 Degrees of protection provided by enclosures (IP Code)
    Consolidated Edition

-   IEC 60721-4-x TR (Technical Reports).

The features and design of your device will determine which of the above
standards or equivalent methods you should use and whether other
standards are appropriate in addition to or in place of these.

# Electromagnetic Compatibility

Electromagnetic compatibility (EMC) encompasses both emissions
(interference with other electronic devices) and immunity (resistance to
interference, which is created by emissions from other electronic
devices, with the performance of the device). We recommend that you
evaluate the EMC of your device according to IEC 60601-1- 2 Medical
Electrical Equipment \-- Part 1: General Requirements for Safety;
Electromagnetic Compatibility \-- Requirements and Tests (Second
Edition, 2001) or equivalent method.

**Emissions**

> EMC testing should demonstrate that the device will not adversely
> interfere with the performance of other electronic devices, such as
> active implantable devices, e.g., pacemakers and defibrillators.
> Testing should include radio frequency (RF) electromagnetic, low
> frequency magnetic, and conducted emissions.

**Immunity**

> EMC testing should also demonstrate that the device will perform as
> expected in the presence of other electrical and electronic devices or
> other sources of electromagnetic disturbance (EMD) in the intended
> environment of use (immunity). The device should operate in an
> acceptable manner (few EMC standards require operation within
> specification) during and after exposure to various forms of
> electromagnetic disturbance. Immunity testing should include:

-   electrostatic discharge (ESD)

-   radiated RF electromagnetic fields

-   electrical fast transients and bursts

-   surges

-   conducted RF electromagnetic energy

-   voltage dips, short interruptions, and voltage variations on power
    supply input lines

-   low-frequency magnetic fields

-   quasi-static electric fields.

# Acoustic Intensity

We recommend that you measure the sonometer's acoustic output intensity.
See "Information for Manufacturers Seeking Marketing Clearance of
Diagnostic Ultrasound Systems and Transducers"
(<http://www.fda.gov/cdrh/ode/ulstran.pdf>) for the measurement methods
we recommend.

# Non-Clinical Testing

We recommend that you provide:

-   descriptions of algorithms for computing the measurements, e.g.,
    broadband ultrasonic attenuation (BUA) and/or speed of sound (SOS)

-   results of laboratory testing to establish the accuracy and
    precision of measured values

-   bandwidth used in the calculation of attenuation versus frequency
    (for BUA measurement). We recommend that you discuss the algorithm
    in detail (e.g., log spectral difference, centroid shift).

-   specification of marker on the pulse waveform for measuring transit
    times for SOS computation (e.g., first zero crossing, envelope
    maximum, first zero crossing prior to the envelope maximum,
    threshold value)

-   explanation of purposes and implementations of any filters applied
    to the received data

-   description of procedures and testing performed to validate quality
    assurance tests

-   analysis of the long-term stability of acoustic properties of test
    objects

-   validation of your recommended method for cleaning and disinfecting
    the system between patients.

# Clinical Testing

We recommend you conduct clinical studies for generating reference
databases (described below) and assessing reproducibility for all bone
sonometers. For these studies, and any other clinical studies you
conduct in support of your 510(k), we recommend you provide the
information described in this section.

**Study Design**

> We recommend you describe, in detail, the study design, including the
> number of sites, any randomization, and control arms.

**Subjects Enrolled**

> We recommend that you show the number of subjects enrolled in the
> study, segregated by:

-   gender

-   ethnic origin

-   disease category

-   age range

-   principal inclusion and exclusion criteria

-   unusual inclusion and exclusion criteria.

    **Methodology**

> We recommend you include a detailed description of the methodology you
> used in gathering clinical data.

**Exclusion Criteria**

> For all of the clinical studies described in this guidance, we
> recommend the exclusion criteria listed below.
>
> ***Current or recent use of bone-active drugs***
>
> We recommend that your exclusion criteria include:

-   any use of bisphosphonates for more than 1 week

    -   calcitonin, within 3 months

    -   therapeutic doses (\>1000 I.U. daily) of vitamin D, within 6
        months

    -   estrogens or selective estrogen receptor modulator (SERM) within
        6 months

    -   therapeutic doses (\> 2 mg/day) fluoride within 3 years

    -   drugs under research protocols within 2 years

    -   unstudied or unapproved drugs.

> ***Presence of metabolic bone disease***
>
> We recommend that your exclusion criteria include:

-   hyper- or hypo-parathyroidism within 5 years

-   osteitis deformans (Paget\'s disease of bone)

-   renal osteodystrophy

-   osteomalacia.

> ***Other diseases or drugs***
>
> We recommend that your exclusion criteria include:

-   gastrointestinal malabsorption

-   liver disorders

-   chronic renal disease

-   unstabilized hyper- or hypothyroidism

-   hyper- or hypoadrenocorticism

-   concomitant use of oral corticosteroids, any dose

-   use of oral corticosteroids within past 6 months, if less than
    equivalent of 7.5 mg daily of prednisone, or use of a greater
    dosage, within the past year

-   use within past 6 months of anti-seizure drugs, barbiturates, or
    anticoagulants

-   stroke with total or partial paralysis with residual disability
    lasting more than 3 months.

    **Diagnostic Measurements**

    We recommend that you provide:

```{=html}
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```
-   rationales and formulas (such as linear combinations) for indexes
    that are derived from acoustic measurements

-   description of the algorithms used to calculate the values presented
    (T-scores, Z-scores, etc.)

-   copies of all pages of test results that are displayed either on a
    monitor or printed out as hard copy.

> **Reference Databases**
>
> Reference databases are used to calculate T and Z scores. These scores
> facilitate diagnostic interpretation of measurements. Diagnostic
> measurements on bone are often expressed as T-scores and Z-scores
> because relative (i.e., dimensionless) values like T-scores and
> Z-scores are easier for the physician to interpret than absolute
> values of measurements like bone density, broadband ultrasound
> attenuation, or speed of sound.
>
> The T-score expresses a measurement relative to a normal reference
> database of healthy young Caucasian females. The Z-score expresses a
> measurement relative to a normal reference database of an individual's
> peer group.
>
> Bone sonometers indicated for determining the possible presence of
> osteoporosis should incorporate a normative reference database for
> T-scores. Bone sonometers for other indications should have both a
> T-score and Z-score reference database.
>
> [T-Score]{.underline}
>
> The World Health Organization (WHO) defines osteoporosis, not by
> absolute values but by T-score (T-score \< -2.5).[^6] T-score, as used
> by WHO in their definition of osteoporosis, is the patient\'s
> measurement minus the average measurement of healthy young (between
> ages 20 and 39) Caucasian females divided by this group\'s standard
> deviation. We believe reference databases of non-Caucasian females or
> males of any ethnicity are not appropriate for T-score calculation,
> unless you also develop new diagnostic values (i.e., cutoffs) for
> osteoporosis or osteopenia, and present the mean and standard
> deviation for each decade cohort.
>
> We recommend that you develop a normative reference database of at
> least 300 healthy Caucasian women between the ages of 20 and 39 with
> at least 150 subjects in each decade.[^7] We recommend that you use at
> least two geographically separated sites.
>
> [Z-Score]{.underline}
>
> Z-score is the patient\'s measurement minus the average measurement
> for those in the same age decade, gender, and ethnicity divided by
> this group\'s standard deviation. We believe databases for different
> ethnicity and genders are appropriate. We recommend that you provide
> gender- and ethnic-specific normative databases, across all ages
> within the range of interest (generally from 20 to 80 or 90), to
> facilitate interpretation of bone measurements for evaluating
> secondary (non-age related) causes of low bone mass.
>
> Databases for each ethnicity and gender should consist of measurement
> results from at least 50 subjects per institution per decade for the
> range of decades of interest. We recommend that you use at least two
> geographically separated sites. We recommend that you analyze the
> databases by decade and present the mean and standard deviation of the
> appropriate bone sonometer measurement for each decade.
>
> If a clinical study is conducted prior to obtaining 510(k) clearance
> of the device, the study must be conducted under the Investigational
> Device Exemptions (IDE) regulation, 21 CFR Part 812. We believe that
> generally, the bone sonometer addressed by this guidance document is a
> non-significant risk device, therefore the studies to obtain reference
> databases are subject to the abbreviated requirements of 21 CFR
> 812.2(b).[^8] In addition to the requirements of section 21 CFR
> 812.2(b), sponsors of such trials must comply with the regulations
> governing institutional review boards (21 CFR Part 56) and informed
> consent (21 CFR Part 50).
>
> **Reproducibility Studies**
>
> These studies define the clinical precision of the device. For
> monitoring indications, the expected change in a patient\'s
> measurement over a given time interval establishes the appropriate
> level of precision. For all indications, we recommend that you
> establish reproducibility with respect to measurement-to-measurement,
> device-to-device, and operator-to-operator variability.
>
> We recommend that you describe your variability studies and include
> methods, a line listing of data, and analyses. We also recommend that
> you provide a brief rationale supporting the statistical validity of
> your analyses. Your variability studies should include both phantom
> and clinical studies or an explanation why one or the other is not
> appropriate.
>
> We recommend that you use at least 3 operators and 3 devices to
> estimate the repositioning, inter-operator, and device-to-device
> variability for ultrasound measurements. We recommend you conduct this
> study on at least 6 pre-menopausal Caucasian women (20 to 45 years of
> age) and at least 6 post-menopausal Caucasian women (aged 55 to 80
> years). Subjects should be distributed throughout each of these age
> ranges. We believe the most efficient design entails each subject
> being measured in duplicate (with repositioning between measurements)
> by each combination of operators and devices.
>
> We recommend that you segregate your data into two age groups (below
> 45 and above 55) and analyze the results separately to obtain the
> variance components for operator, device, and repositioning, as well
> as the combined variability. These in turn should be used to obtain
> the corresponding coefficients of variation. If you demonstrate the
> results are combinable across age groups, then it is appropriate to
> pool all the data. We also recommend that you present the combined
> variability as a fraction of the standard deviation of the young
> normal reference group or T-score standard deviation (TSD). The
> T-score of an individual +/- 2 TSD provides an approximate 95%
> confidence interval on the measured T-score.
>
> For monitoring indications, we recommend that you specify the
> frequency of monitoring and show that the overall precision of the
> device measurement allows for that frequency over a specified time
> interval.

While, in general, additional clinical studies will not be needed for
most bone sonometer devices, FDA may recommend that you collect clinical
data to demonstrate the effectiveness for a bone sonometer with any one
of the following:

-   indications for use dissimilar from indications for use of legally
    marketed bone sonometers of the same type

-   designs dissimilar from designs previously cleared under a premarket
    notification

-   new technology, i.e., technology different from that used in legally
    marketed bone sonometers.

FDA will always consider alternatives to clinical testing when the
proposed alternatives are supported by an adequate scientific rationale.
If you conduct any additional clinical studies, we recommend you
describe the design, conduct, and results of the clinical studies and
follow the recommendations above for reference databases and
reproducibility.

# Labeling 

The premarket notification should include labeling in sufficient detail
to satisfy the requirements of 21 CFR 807.87(e). The following
suggestions are aimed at assisting you in preparing labeling that
satisfies the requirements of 21 CFR 807.87(e).[^9]

> **Indications for Use**
>
> We recommend that the indications for use specify the target
> population and include one or more of the following elements:

-   determining the possible presence of osteoporosis and assessing
    fracture risk

-   monitoring bone changes over time

-   assessing non-age-related bone loss.

> For example:
>
> The device performs a quantitative ultrasound measurement of bone, the
> results of which can be used in conjunction with other clinical risk
> factors as an aid to the physician in the diagnosis of osteoporosis
> and medical conditions leading to reduced bone density, and ultimately
> in the assessment of fracture risk.
>
> **Contraindications**
>
> We recommend that the labeling list all contraindications, if any.
>
> **Warnings**
>
> We recommend that the labeling include warnings against using the
> device on skin with open wounds or signs of trauma, bleeding, or
> infection.
>
> **Directions for Use**
>
> As a prescription device, under 21 CFR 801.109, the device is exempt
> from having adequate directions for lay use. Nevertheless, we
> recommend providing clear and concise instructions for professional
> users that delineate the technological features of the specific device
> and how the device is to be used on patients. Instructions should
> encourage local/institutional training programs designed to
> familiarize users with the features of the device and how to use it in
> a safe and effective manner.
>
> We recommend that the instructions also include:

-   a protocol for cleaning and disinfecting between patients, including
    a list of any accessories needed to clean and disinfect the device
    and the chemical name of the recommended germicide

-   methods for preparing the skin (e.g., cleaning with alcohol pads)

-   methods for ensuring good coupling between the ultrasound transducer
    and the skin surface (e.g., use of coupling gel for dry systems and
    eliminating bubbles for wet systems)

-   recommendations for quality assurance methods

-   maximum period of time over which phantoms or test objects may be
    assumed reliable.

> We also recommend that the instructions emphasize the need to use the
> same healthy young Caucasian female database for the calculation of
> every patient\'s T-score, regardless of gender and ethnicity and
> advise against the use of gender- and ethnic-specific normative data
> for fracture risk assessment.
>
> **Device Description**
>
> We recommend that labeling identify the:

-   anatomical site(s) scanned

-   major components of system

-   ultrasound parameter(s) being used

-   scanning method.

> **Precautions**
>
> We recommend that the labeling:

-   list possible adverse events associated with the use of this device

-   caution against the use of different calibration phantoms in
    monitoring.

> **Individualization of Treatment**
>
> We recommend that labeling advise users that the device is **[not
> limited]{.underline}** to use in Caucasian women. For example, "This
> device may be used to determine the possible presence of osteoporosis
> and to estimate fracture risk in men and in Caucasian and
> non-Caucasian women. You should use the same young normal Caucasian
> female database to calculate the T-score for all patients, regardless
> of gender and ethnicity."
>
> We also recommend that labeling address gender and ethnicity in
> monitoring bone changes over time, for example, "There are similarly
> no gender or ethnic restrictions on its use in monitoring bone changes
> over time or assessing non-age-related bone loss, although for the
> latter assessment, you should use databases that are matched to the
> patient\'s age, gender, and ethnicity."
>
> **Clinical Studies**
>
> Information in this section should include a brief summary, i.e., a
> self-contained description of the design, conduct, and results of the
> clinical studies for generation of the reference database and
> assessment of precision. The summary should include the information
> described below.
>
> ***Study Design***
>
> We recommend that labeling briefly describe the study design, in
> particular, by addressing the number of sites, any randomization,
> control arms, etc.
>
> ***Subjects Enrolled***
>
> We recommend that your labeling show the number of subjects enrolled
> in the study, segregated by:

-   gender

-   ethnic origin

-   disease category

-   age range

-   principal and unusual inclusion and exclusion criteria.

> ***Methodology***
>
> We recommend that labeling include a concise statement of the
> methodology used in gathering the effectiveness and safety data.
>
> **User Manual, Technical Manual, and Other Labeling**
>
> ***Physician Information***
>
> We recommend that the physician labeling discuss:

-   osteoporosis

-   different methods of measuring bone strength

-   error and precision of these measurements

-   interpretation of results (e.g., differences in patient
    classification are possible for two different methods).

-   precision of the device

-   appropriate monitoring interval, if used for monitoring patients
    under treatment

-   references to publications on the differences of results from the
    various bone densitometers and sonometers.

> We also recommend that the physician labeling describe a quality
> assurance program for the user that assures the continued proper
> operation and calibration of the device. It should include the
> conditions (e.g., duration of use, component replacement, quality
> control and calibration procedures) that should be managed during
> normal use to maintain the safety and effectiveness of the device.
>
> ***Patient Labeling***
>
> We recommend that the patient labeling explain:

-   osteoporosis

-   why the disease is of concern to women

-   the measurement of bone using ultrasound.

> We also recommend that the patient labeling explain that ultrasound
> measurements are different from x-ray bone densitometry (e.g., How
> does it work? What will it tell me? Why is this important? What other
> tests are available and how does your device differ? What should the
> patient know?). (See also **Guidance on Medical Device Patient
> Labeling**, <http://www.fda.gov/cdrh/ohip/guidance/1128.html>.)

[^1]: Refer to
    [http://www.fda.gov/cdrh/ode/indicate.html](http://www.fda.gov/cdrh/ode/indicate.pdf)
    for the recommended format.

[^2]: If FDA makes a substantial equivalence determination based on
    acceptance criteria, the subject device should be tested and shown
    to meet these acceptance criteria before being introduced into
    interstate commerce. If the finished device does not meet the
    acceptance criteria and, thus, differs from the device described in
    the cleared 510(k), FDA recommends that submitters apply the same
    criteria used to assess modifications to legally marketed devices
    (21 CFR 807.81(a)(3)) to determine whether marketing of the finished
    device requires clearance of a new 510(k).

[^3]: See Required Elements for a Declaration of Conformity to a
    Recognized Standard (Screening Checklist for All Premarket
    Notification \[510(K)\] Submissions),
    [http://www.fda.gov/cdrh/ode/reqrecstand.html]{.underline}.

[^4]: Under the authority of 21 CFR 1002.50(b), diagnostic ultrasound
    products are exempt from the reporting requirements of 21 CFR
    1002.10 and 1002.12, if a 510(k) has been submitted. See also
    "**Appendix D Exemption from Reporting Under 21 CFR 1002"** in
    **Information for Manufacturers Seeking Marketing Clearance of
    Diagnostic Ultrasound Systems and Transducers**, September 30, 1997
    (<http://www.fda.gov/cdrh/ode/ulstran.pdf> ). However, these devices
    remain subject to the reporting requirements identified in 21 CFR
    1002.20 Reporting of accidental radiation occurrences, 21 CFR Part
    1003 Notification of Defects, and 21 CFR Part 1004 Repurchase,
    repairs, or replacement of electronic products.

[^5]: <http://www.fda.gov/cdrh/mdufma/guidance/1215.html>.

[^6]: *Assessment of Fracture Risk and Its Application to Screening for
    Postmenopausal Osteoporosis*, World Health Organization, WHO
    Technical Report Series 843, 1994.

[^7]: The optimal range is 300 to 500 subjects according to Martin et
    al., [Normal Values in Clinical Chemistry]{.underline}, Marcel
    Dekker, 1975, pages 51-52.

[^8]: See
    [[http://www.fda.gov/oc/ohrt/irbs/devices.html#risk]{.underline}](http://www.fda.gov/oc/ohrt/irbs/devices.html#risk).

[^9]: Although final labeling is not required for 510(k) clearance,
    final labeling must comply with the requirements of 21 CFR 801
    before a medical device is introduced into interstate commerce. In
    addition, final labeling for prescription medical devices must
    comply with 21 CFR 801.109. Labeling recommendations in this
    guidance are consistent with the requirements of part 801.