Orthopaedic and Rehabilitation Devices Panel

Of the Medical Devices Advisory Committee

November 21, 2002

Draft Questions

[SPINE]{.underline}

In January of 2000, the FDA issued The Guidance Document for the
Preparation of IDEs for spinal systems. Prior to its issuance, ORDB
presented a preliminary background document to the Orthopedic and
Rehabilitation Devices Panel. During the October 8, 1998 panel meeting,
input was received from panel members and the public which resulted in
the current guidance document. At that time, the FDA requested some
input on Non-Fusion devices which are *not* intended to facilitate
fusion of the spine. Unlike fusion devices, these devices allow some
functional motion through the various levels of the spine. These include
devices that provide stability while continuing to allow some percentage
of normal or functional motion, devices which allow motion and growth,
and devices which stabilize vertebral body and spine fracture repair.
Examples of these types of devices are included in the references
enclosed in this panel package.

The current spinal guidance focuses primarily on spinal fusion devices
for various etiologies, with brief guidance on such non fusion devices
as vertebral body replacements and disc replacement devices. While the
FDA Guidance for Spinal Implant 510 (k)s issued September 27, 2000,
outlines in detail devices intended for fusion and there is a voluntary
testing standard available for pedicle screw systems and intervertebral
body fusion devices (i.e., ASTM F1717 and ASTM 2077, respectively), many
sponsors use modified versions to address different types of spinal
systems. Because there are testing standards in development, the FDA has
advised sponsors to contact appropriate standards bodies (e.g., ASTM,
ISO) for additional information. As the scope of spinal devices expands,
the FDA recognizes the need to update the spinal guidance to include
additional clarification and suggestions for preclinical testing,
clinical assessments, endpoints and success determinations related to
emerging spinal technologies.

**[I. Preclinical Questions]{.underline}**

1.  Currently, the FDA Guidance for Spinal Implant 510(k)'s, which
    extensively covers devices intended for fusion, recommends various
    static and fatigue testing for spinal devices. Because devices not
    intended for fusion are intended to stabilize the spinal motion
    segment and retain functional motion, they must be designed to last
    for the lifetime of the individual rather than until a fusion
    occurs. Therefore, the current testing requested for devices
    intended for non-fusion may not be adequate. In addition, the
    current testing for fusion devices made of materials other than
    stainless steel and titanium may not be adequate. The FDA currently
    requests the following testing for spinal devices:

> **Fusion devices** (devices intended to stabilize by fusing motion
> segments, e.g., pedicle screw systems, intervertebral fusion devices,
> vertebral body fusion devices, etc.)

-   [Fatigue]{.underline} - The fatigue testing should involve a minimum
    of six samples of the worst case construct to generate a stress
    (load) versus number of cycles (S/N) curve that characterizes the
    asymptotic endurance limit (e.g., a minimum of two samples per load
    level with one load level reaching a run out value of
    [five]{.underline} million cycles) compared to a appropriate control
    device. Rationale for the components chosen as worst case should be
    provided. The interconnection mechanisms/systems may be tested in
    the same set of constructs or each in a separate set of constructs.
    Each interconnection mechanism should be tested or an adequate
    rationale for not testing an interconnection should be provided.
    Additionally, testing should be performed out to a minimum run out
    of 10 million cycles for intervertebral body replacement devices
    intended for tumor patients because these patients may present a
    great difficulty in achieving fusion, and, therefore, the device is
    acting more as a stabilizer.

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-   [Static]{.underline} - The testing should involve a minimum of five
    samples of the worst case construct. As with the fatigue testing,
    the components tested and the loading mode should be justified.

> Examples of the types of construct testing typically performed for a
> given type of spinal system in order to establish relative safety are
> as follows:
>
> • For lumbar and thoracic pedicle screw systems that are intended for
> fusion, static and fatigue bending testing should be provided (e.g.,
> ASTM F1717).
>
> • For cervical, pedicle or lateral mass systems intended for fusion,
> static and fatigue testing should be provided. The loading mode
> (torsional or bending) is dependent on the design and material.
>
> • For intervertebral body fusion devices, static, fatigue, and
> expulsion (push-out testing) testing should be provided. The loading
> mode (axial, torsional, bending, and/or shear) is dependent on the
> design, material, and levels of use.
>
> • For vertebral body replacement devices, static and fatigue testing
> in bending and torsional loading modes should be provided.
>
> **Non-Fusion devices** (devices intended to stabilize yet retain
> functional motion, e.g., disc nucleus replacements, intervertebral
> disc prosthesis, screw or hook based stabilization spinal systems
> without attempting fusion)
>
> These are some of the items FDA believes may be appropriate to
> consider:
>
> • [Compression Fatigue]{.underline} - The fatigue testing should
> involve a minimum of six samples of the worst case construct to
> generate a stress (load) versus number of cycles (S/N) curve that
> characterizes the asymptotic endurance limit (e.g., a minimum of two
> samples per load level with one load level reaching a run out value of
> [ten]{.underline} million cycles) compared to a appropriate control
> device. Rationale for the components chosen as worst case should be
> provided.

-   [Durability Testing]{.underline} -- The durability testing should
    involve cyclic loading testing several loading modes (e.g.,
    flexion/extension, lateral bending, and axial rotation) and involve
    a minimum of six samples of the worst-case construct out to
    [ten]{.underline} million cycles. This test can either be combined
    to incorporate all testing directions into one test, or separated
    into each loading mode. Durability testing establishes loading
    direction, stability of the device, and wear generation potential.
    Clinical justification for the loads and angles chosen should be
    provided.

> • [Static Compression]{.underline} - The testing should involve a
> minimum of five samples of the worst case construct. As with the
> fatigue testing, the components tested and the loading mode should be
> justified.

-   [Other potential tests]{.underline} --

-   Migration/Expulsion testing

-   Static and Dynamic Shear Testing

-   Creep and Stress Relaxation Testing

> Examples of the types of construct testing typically performed for a
> given type of spinal system in order to establish relative safety are
> as follows:
>
> • For vertebral disc replacements, static and fatigue tests in
> multiple loading modes should be provided out to 10 million cycles.

-   For a stabilization pedicle screw system intended for non-fusion,
    dynamic shear testing and torsion testing should be provided.

-   For nucleus replacements, expulsion testing should be provided.

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-   For nucleus replacements, fatigue compression tests on new and
    "aged" devices should be provided.

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-   For devices with polymer components (e.g., polyethylene cords,
    poyletheretherketone components, etc) creep and/or stress relaxation
    testing should be provided.

> Depending on the design of the system, the sponsor may need to perform
> different tests in lieu of those identified above, perform additional
> tests in different testing modes, provide testing on individual
> components of the subject system, etc.
>
> While there is a voluntary testing standard available for pedicle
> screw systems intended for fusion and intervertebral body fusion
> devices (i.e., ASTM F1717 and ASTM 2077, respectively), many sponsors
> use modified versions to address different types of spinal systems.
> Because there are testing standards in development, sponsors are
> advised to contact appropriate standards bodies (e.g., ASTM, ISO) for
> information regarding test set-ups, parameters, etc. for their
> specific device type.

-   Please comment on the currently recommended preclinical mechanical,
    debris, or wear testing to evaluate new materials, device
    properties/integrity and wear debris for fusion and non-fusion
    devices.

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-   Discuss what additional testing, if any, should be added to current
    testing recommendations for the following devices

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-   Stabilization devices for non-fusion

-   Intervertebral disc/joint replacements (cervical/thoracolumbar)

-   Devices manufactured out of new materials.

-   Intervertebral disc nucleus replacements

2.  The FDA is currently requesting information for any device used in
    the area of the spinal cord and nerve roots, that has the potential
    to generate debris, regarding local and systemic adverse effects.
    For those incorporating new materials (e.g.., polymers, composites,
    etc.) or designs, both fusion and non fusion, the FDA recommends
    that manufacturers perform wear simulations and fatigue tests to
    evaluate the potential for the device to generate wear debris. The
    FDA believes the wear debris generated from these tests should be
    collected and characterized. For those devices where this may be an
    issue, the FDA suggests two options:

-   Injection study of various sized particles into the spinal cord area
    of small animals

-   Functional animal models

> Because of the limitations of the current testing methods and models,
> should devices made of new materials and/or those intended to retain
> motion be tested for local and systemic adverse effects independent of
> the type of material or the amount of wear debris generated? If you
> suggest that testing be performed, please describe the testing you
> recommend. For example,

-   Discuss viability and usefulness of injection animal study including
    amount and distribution of sizes and shapes of wear debris should be
    injected in the animal in predicting what may occur clinically for
    the life of the implant;

-   Discuss recommendations, viability and usefulness of functional
    animal models in predicting what may occur clinically for the life
    of the implant; or

-   Discuss alternatives.

**[II. Clinical Questions]{.underline}**

1\. For spinal assemblies not intended to fuse motion segments
(Non-fusion spinal devices, e.g., disc replacement devices, nucleus
replacement devices, joint replacement, spinal stabilization without
fusion, etc.), the goals of treatment may be to stabilize the spine,
maintain "normal/functional" motion, treat disease early in its course
to prevent further progression and to conserve motion instead of fusing
segments of the spine to alleviate pain and restore function. These
types of devices provide challenges in choosing the best methods to
evaluate safety and effectiveness.

Our current Spinal Guidance describes methods to assure that data
collected provide adequate characterization of the safety and
effectiveness of devices. These sections suggest appropriate patient
inclusion and exclusion criteria (Section 4 and 5), effectiveness
evaluations (Section 8: 8.1-8.4) safety evaluations (Section 9) and
patient and study success criteria (Section 10). The FDA believes that
the populations and goals of treatment may be different for devices that
maintain functional motion. Therefore:

a.  Please discuss study designs which may be better suited to evaluate
    Non-Fusion spinal devices. In your discussion, please comment on:

    i.  enrollment criteria,

    ii. patient populations,

    iii. controls,

    iv. success criteria and

    v.  goals of the study

that would be suitable for these types of Non-fusion spinal devices.

b.  Devices intended to stabilize the spine yet retain functional motion
    are expected to have an upper limit of motion beyond which one would
    consider the device to be unstable and a lower limit below which one
    would consider the device to have inadequate motion or possibly even
    consider the segment to be fused. Please discuss the amount of
    motion and on what scale, to define a patient as a functional and
    clinical success (i.e., a clinically significant improvement in
    condition) for each of cervical, thoracic and lumbar levels for
    Non-Fusion spinal devices.

**[III. Vertebroplasty (see enclosed references)]{.underline}**

There is a growing body of literature describing devices to be used for
the treatment of insufficiency fractures due to neoplasm or
osteoporosis, either for stabilization or reduction of the fracture.
These devices include high and low modulus bone cements and other
non-resorbable and absorbable bone cement alternatives. As with other
devices, these devices and procedures are emerging as new technologies
for treating fractures in the spine, and the FDA considers these devices
as permanent implants in the spine.

1.  Describe the current treatment alternatives for the treatment of
    insufficiency fractures due to neoplasm or osteoporosis, and the
    timeframe of conservative treatment before additional intervention
    is considered.

2.  In the study of devices for the treatment of insufficiency fractures
    due to neoplasm or osteoporosis, either for stabilization or
    reduction of the fracture, please discuss appropriate control groups
    and describe appropriate timeframes for comparison of safety
    outcomes and effectiveness outcomes. Based upon your recommendations
    regarding appropriate control groups and timeframes for safety and
    effectiveness comparisons, when would be appropriate for control
    treatment to continue before allowing patients to crossover to the
    treatment group?

3.  Many of the devices used in vertebroplasty (e.g., high and low
    modulus bone cements and other non-resorbable and absorbable bone
    cement alternatives) are polymerized in situ and have either toxic
    monomers, copolymers, accelerators, or initiators. In addition to
    the adverse events known to occur with devices used in
    vertebroplasty, the FDA currently asks sponsors to collect
    additional information on specific aspects of safety including
    infection, neurological status and radiographic endpoints evaluating
    extravasations, adjacent fractures, osteolysis, fracture through the
    material at the level of repair, adjacent arthritis, secondary
    interventions, progression of disease and fusion at the level of
    treatment.

-   What animal study or clinical study time point(s) should be
    considered in evaluation of chemical and toxic effects of the device
    for short and long term implantation of the device?

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-   Please discuss any additional safety assessments you feel are
    valuable for evaluating these implants,

4.  The FDA currently asks that spine studies collect information on
    specific aspects of effectiveness using such tools as the pain
    scales, function/disability questionnaires (NDI and Oswestry),
    maintenance of neurological status, maintenance of vertebral height,
    and a quality of Life (SF-36, WOMAC) questionnaire.

5.  

-   Please discuss what clinically relevant endpoints in clinical
    practice should be measured to prove efficacy for these types of
    products.

-   Please discuss the distribution of expected improvement in these
    evaluations

-   Please discuss at what point you would expect maximum level of
    improvement to occur using each of these assessment tools.

-   Please discuss any additional effectiveness assessments you feel are
    valuable for these implants,

-   Please discuss what degree of improvements would be expected as
    clinically significant for the successful use of these devices.