**Draft Guidance for Industry and FDA Staff**

**Class II Special Controls Guidance Document: Vascular and
Neurovascular Embolization Devices**

***Draft Guidance***

**This guidance document is being distributed for comment purposes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

**Document issued on: \[release date of FR Notice\]**

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notice announcing the availability of the draft guidance document.
Submit comments to Dockets Management Branch (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. 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 draft document, contact Peter L. Hudson,
Ph.D., Plastic and Reconstructive Surgery Branch, 301-594-3090, ext.194
or <plh@cdrh.fda.gov>, Elisa D. Harvey, D.V.M., Ph.D., Peripheral
Vascular Devices Branch, 301-443-8262, ext. 167 or <edh@cdrh.fda.gov>,
or Colin M. Pollard, Obstetrics and Gynecology Devices Branch, (301)
594-1180 or <CMP@cdrh.fda.gov>.

**When final, this document will supersede "Guidance for Neurological
Embolization Devices" dated November 1, 2000.**

![](media/image1.png)

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

**Food and Drug Administration**

**Center for Devices and Radiological Health**

**Office of Device Evaluation**

**Peripheral Vascular Devices Branch, Division of Cardiovascular
Devices**

**Plastic and Reconstructive Surgery Devices Branch, Division of
General, Restorative, and Neurological Devices**

**Obstetrics and Gynecology Devices Branch, Division of Reproductive,
Abdominal and Radiological Devices**

**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
(**1234**) 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
3](#the-content-and-format-of-an-abbreviated-510k-submission)

[4. Scope 6](#scope)

[5. Device Description 7](#device-description)

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

[7. Preclinical Testing 9](#preclinical-testing)

[8. Sterility 11](#sterility)

[9. Animal Testing 11](#animal-testing)

[10. Clinical Testing 12](#clinical-testing)

[11. Labeling 15](#labeling)

**Draft Guidance for Industry and FDA Staff**

#### 

**Class II Special Controls Guidance Document: Vascular Embolization
Devices and Neurovascular Embolization Devices**

***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.***

# 1. Introduction

This draft guidance document was developed as a special controls
guidance document to support the reclassification of the vascular
embolization device and the neurovascular embolization device into class
II.

The vascular embolization device, as proposed, is intended to control
hemorrhaging due to aneurysms, certain types of tumors (e.g., nephroma,
hepatoma, and fibroids), and arteriovenous malformations. The
neurovascular embolization device, as proposed, is intended to
permanently occlude blood flow to cerebral aneurysms and cerebral
arteriovenous malformations.

FDA believes that the risks to health associated with the intended uses
of the vascular embolization and the neurovascular embolization devices
are the same, therefore, FDA believes that a single guidance document
can serve as the special control for both device types.

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

Following the effective date of a final rule reclassifying these
devices, any firm submitting a premarket notification (510(k)) for a
vascular embolization device or a neurovascular embolization device will
need to address the risks identified in the special control guidance
document. However, the firm need only show that its device meets the
recommendations of the guidance document or in some other way provides
equivalent assurances of safety and effectiveness.

FDA\'s guidance documents, including this guidance, do not establish
legally enforceable responsibilities. Instead, guidance documents
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 guidance
documents means that something is suggested or recommended, but not
required.

# 2. 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 the vascular embolization device and the
> neurovascular embolization device. Thus, a manufacturer who intends to
> market a device of one of these generic types should (1) conform to
> the general controls of the Federal Food, Drug, & 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 these devices identified in this guidance document,
> and (3) obtain a substantial equivalence determination from FDA prior
> to marketing the device.

This special control guidance document identifies the classification
regulations and product codes for these devices (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
devices and lead to a timely 510(k) review and clearance. This document
supplements other FDA documents regarding the specific content
requirements of a 510(k) submission. You should also refer to CDRH's
**Device Advice** <http://www.fda.gov/cdrh/devadvice/> and 21 CFR §
807.87.

As described in the guidance document 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 a class II special controls guidance
document has been issued. Manufacturers considering modifications to
their own cleared devices may lessen the regulatory burden by submitting
a Special 510(k).

# 3. 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 21 CFR § 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. (Refer to Section 11 for
> specific information that should be included in the labeling for
> devices of the types covered by this guidance document.)
>
> **Summary report**

We recommend that the summary report contain:

-   A description of the device and its intended use. We recommend that
    the description include a complete discussion of the performance
    specifications and, when appropriate, detailed, labeled drawings of
    the device. (Refer to Section 5 for specific information that we
    recommend you include in the device description for devices of the
    types covered by this guidance document.) You should also submit an
    \"indications for use\" enclosure.[^1]

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-   A description of device design requirements.

-   Identification of the Risk Analysis method(s) used to assess the
    risk profile in general as well as the specific device's design and
    the results of this analysis. (Refer to Section 6 for the risks to
    health generally associated with the use of this device that FDA has
    identified.)

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-   A discussion of 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.

-   A brief description of the test method(s) you have used or intend to
    use to address each performance aspect identified in Sections 7-11
    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.)

-   If any part of the device design or testing relies on a recognized
    standard, (1) a statement that testing will be conducted and meet
    specified acceptance criteria before the product is marketed, or (2)
    a declaration of conformity to the standard.[^3] [Please note that
    testing must be completed before submitting a declaration of
    conformity to a recognized standard]{.underline}. (Section
    514(c)(1)(B) of the Act). For more information, refer to the FDA
    guidance document, **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 document.
A Traditional 510(k) should include all of your methods, data,
acceptance criteria, and conclusions. Manufacturers considering
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 510(k)
submission for a vascular embolization device or a neurovascular
embolization device. The recommendations made in this guidance document
apply to both, unless vascular or neurovascular is specified.

# 4. Scope 

The scope of this document is limited to the following two device types:

+-------------+-----------+------------------+-------------------------+
| **Device    | **Class   | **Product Code** | **Examples**            |
| Type**      | ification |                  |                         |
|             | Reg       |                  |                         |
|             | ulation** |                  |                         |
|             | (21 CFR)  |                  |                         |
+-------------+-----------+------------------+-------------------------+
| Vascular    | §         | KRD device,      | -   embolization coils  |
| e           | 870.3300  | embolization,    |                         |
| mbolization |           | arterial         | ```{=html}              |
| device      |           |                  | <!-- -->                |
|             |           |                  | ```                     |
|             |           |                  | -   detachable balloons |
|             |           |                  |                         |
|             |           |                  | -   polyvinyl alcohol   |
|             |           |                  |     particles           |
|             |           |                  |                         |
|             |           |                  | -   nonresorbable       |
|             |           |                  |     particles           |
+-------------+-----------+------------------+-------------------------+
|             |           | NAJ agents,      | -   nonresorbable       |
|             |           | embolic, for     |     particles           |
|             |           | treatment of     |                         |
|             |           | uterine fibroids |                         |
+-------------+-----------+------------------+-------------------------+
| Ne          | §         | HCG device,      | -   embolization coils  |
| urovascular | 882.5950  | artificial       |                         |
| e           |           | embolization     | -   polyvinyl alcohol   |
| mbolization |           |                  |     particles           |
| device      |           |                  |                         |
|             |           |                  | -   nonresorbable       |
|             |           |                  |     particles           |
+-------------+-----------+------------------+-------------------------+
|             |           | MZQ balloon,     | -   detachable balloons |
|             |           | detachable, for  |                         |
|             |           | neurovascular    |                         |
|             |           | occlusion        |                         |
+-------------+-----------+------------------+-------------------------+

In the companion proposed rule, FDA is proposing the revisions below to
the names and identifications of these embolization device types, §§
870.3300 and 882.5950:

> **§ 870.3300 -- Vascular embolization device.**

(a) *Identification*. A vascular embolization device is an intravascular
    implant intended to control hemorrhaging due to aneurysms, certain
    types of tumors (e.g., nephroma, hepatoma, uterine fibroids), and
    arteriovenous malformations. This does not include cyanoacrylates
    and other embolic agents, which act by polymerization or
    precipitation. Embolization devices used in neurovascular
    applications are also not included in this classification, see 21
    CFR 882.5950.

> *(b) Classification*. Class II (special controls). The special control
> for the device is FDA's "Class II Special Controls Guidance Document:
> Vascular and Neurovascular Embolization Devices."

**§ 882.5950 -- Neurovascular embolization device.**

(a) *Identification*. A neurovascular embolization device is an
    intravascular implant intended to permanently occlude blood flow to
    cerebral aneurysms and cerebral arteriovenous malformations. This
    does not include cyanoacrylates and other embolic agents, which act
    by polymerization or precipitation. Embolization devices used in
    other vascular applications are also not included in this
    classification, see 21 CFR 870.3300.

(b) *Classification*. Class II (special controls). The special control
    for the device is FDA's "Class II Special Controls Guidance
    Document: Vascular and Neurovascular Embolization Devices."

Cyanoacrylates and other embolic devices (product code NPE), which act
by polymerization or precipitation, continue to be regulated as
postamendments class III devices and require premarket approval (PMA)
applications.

# 5. Device Description

We recommend that you identify your device by regulation number and
product code and include the following information:

-   identity of the reagents and raw materials (i.e., reagent source,
    purity, Certificates of Analyses (CoA), or Material Safety Data
    Sheets, (MSDS)) used in the construction of the device and any
    voluntary material conformity standards

-   identity and quantity of any manufacturing reagent (e.g., organic
    solvents, heavy metals, cross-linking reagents remaining in the
    device) that is potentially toxic

-   a description of the components of the device and its assembly

-   a description of any accessories used with the device, e.g.,
    delivery catheters

-   the range of dimensions, shapes, and device designs

-   engineering drawings

-   a description of the principle of operation (i.e., method of
    deployment and embolization)

-   a description of how the device is provided (e.g., sterile,
    assembled, single use).

# 6. Risks to Health

In the table below, FDA has identified the risks to health generally
associated with the use of the devices 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, prior to submitting your 510(k), to
identify any other risks specific to your device. For example, a device
with gynecological indications may present additional risks, such as
damage to the uterine wall, diffuse uterine necrosis, primary ovarian
failure, reproductive toxicity, or carcinogenicity, as well as other
risks related to the chemistry, toxicology, and healing response in the
uterine environment. The 510(k) should describe the risk analysis
method. 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 risk**        | **Recommended mitigation measures**     |
+----------------------------+-----------------------------------------+
| Blood vessel perforation   | Sections:                               |
| or rupture                 |                                         |
|                            | > 7\. Preclinical Testing               |
|                            | >                                       |
|                            | > 9\. Animal Testing                    |
|                            | >                                       |
|                            | > 10\. Clinical Testing                 |
|                            | >                                       |
|                            | > 11\. Labeling                         |
+----------------------------+-----------------------------------------+
| Unintended thrombosis      | Sections:                               |
|                            |                                         |
|                            | > 7\. Preclinical Testing               |
|                            | >                                       |
|                            | > 9\. Animal Testing                    |
|                            | >                                       |
|                            | > 10\. Clinical Testing                 |
|                            | >                                       |
|                            | > 11\. Labeling                         |
+----------------------------+-----------------------------------------+
| Adverse tissue reaction    | Sections:                               |
|                            |                                         |
|                            | > 7\. Preclinical Testing               |
|                            | >                                       |
|                            | > 9\. Animal Testing                    |
|                            | >                                       |
|                            | > 10\. Clinical Testing                 |
+----------------------------+-----------------------------------------+
| Infection                  | Section 8. Sterility                    |
+----------------------------+-----------------------------------------+
| Hematoma formation         | Sections:                               |
|                            |                                         |
|                            | > 7\. Preclinical Testing               |
|                            | >                                       |
|                            | > 9\. Animal Testing                    |
|                            | >                                       |
|                            | > 10\. Clinical Testing                 |
|                            | >                                       |
|                            | > 11\. Labeling                         |
+----------------------------+-----------------------------------------+

# 7. Preclinical Testing

We recommend that you conduct the preclinical testing below to establish
the performance characteristics of the device.

> *Polyvinyl Alcohol (PVA) Particle Testing*
>
> We recommend that you provide the following for PVA particles:

-   chemical analysis of the final sterilized device, including
    identification and quantification of any processing additives,
    contaminants, etc.

-   if applicable, an explanation of how formaldehyde and/or other
    processing materials are removed from the particles and data
    evaluating the removal process

-   particle size ranges

-   assessment of particle size compatibility with the recommended
    delivery catheter(s)

-   evaluation of the uniform dispersion and suspension of particles
    within the catheter when mixed with the recommended contrast
    agent(s) or other interactive material(s) according to the labeled
    instructions.

> *Detachable Balloon Testing*
>
> We recommend that you provide the following for detachable balloons:

-   the inflation/deflation rates for each balloon size

-   the pressure(s) required to rupture the balloon(s) and the
    specification for the maximum inflation pressure

-   a plot of volume versus inflation pressure

-   the force needed to detach the balloon

-   the balloon permeability

-   the reliability of the detachment mechanism.

> *Embolization Coil Testing*
>
> We recommend that you provide the following for embolization coils:

-   the coil strength (i.e., the force required to deform the coil
    shape)

-   the ease of delivery, as measured by friction when advancing and/or
    retracting the coil through a recommended catheter positioned in a
    simulated tortuosity

-   for coils with fibers, a description of the fiber attachment
    mechanism and pull-out force

-   a description of the detachment mechanism and data on the detachment
    time

-   the reliability of the detachment mechanism.

> *Delivery Catheter Testing*
>
> If your 510(k) includes a new delivery catheter, we recommend that you
> provide the following information for that catheter:

-   tensile strength

-   catheter burst pressure

-   flexibility

-   a plot comparing the flow rate of fluid through the catheter versus
    the applied internal pressure

-   hub attachment strength

-   kink resistance

-   radiopacity

-   coefficient of friction of the external surface of the catheter.

> *Shelf Life*
>
> We recommend that you conduct both preclinical and packaging testing
> to establish the shelf life (i.e., expiration date) of the device as a
> part of the validation activities required by the Quality Systems
> Requirements (21 CFR Part 820). Accelerated test results should be
> supported by validated test information, and, depending on the device
> component, should also be supported by real time test data. For
> mechanical testing, you should conduct both preclinical and packaging
> testing on representative aged samples. For packaging testing, we
> recommend that you conduct testing on the final finished package
> measuring initial integrity and the maintenance of integrity. We
> recommend that you use test methods that are either validated or
> standardized. The documentation from these validation activities must
> be maintained in the Design History File for the device (21 CFR §
> 820.30).
>
> *Biocompatibility*
>
> FDA recommends that you select tests appropriate for implant devices
> with tissue/bone and blood contact as described in the FDA-modified
> **Use of International Standard ISO-10993, Biological Evaluation of
> Medical Devices Part-1: Evaluation and Testing**,
> <http://www.fda.gov/cdrh/g951.html>.
>
> We recommend that you perform carcinogenicity studies with devices in
> which a positive genotoxicity test result was obtained. We recommend
> that you take into consideration identities of the chemical components
> and available information regarding their toxicity in your evaluations
> of potential carcinogenicity.
>
> For neurovascular embolization devices, because ethylene oxide (EO)
> may cause neurotoxicity, in addition to measuring the EO residue
> levels, we recommend that you perform biocompatibility testing on the
> finished EO-sterilized device using intracranial implantation to
> assess any adverse tissue response. You should demonstrate that the
> level of sterilant residues remaining in the device do not raise
> concerns over the safe use of the product.
>
> *Pyrogenicity*
>
> Because of the potential for contact with the intrathecal space, the
> amount of endotoxin in the final, sterilized, neurovascular
> embolization device should be less than 0.06 Endotoxin Unit (EU)/mL
> and in the vascular embolization devices, less than 0.5 EU. These
> recommendations are described in the "Guideline on validation of the
> Limulus Amebocyte Lysate test as an end-product endotoxin test for
> human and animal parenteral drugs, biological products, and medical
> devices," December 1987,
> <http://www.fda.gov/cder/guidance/old005fn.pdf>.

# 8. Sterility

FDA recommends that you provide sterilization information described in
the **Updated 510(k) Sterility Review Guidance K90-1; Final Guidance for
Industry and FDA**, <http://www.fda.gov/cdrh/ode/guidance/361.html>. The
device should be sterile with a sterility assurance level (SAL) of 1 x
10^-6^. Refer to the Biocompatibility section above for testing related
to EO-sterilized devices.

# 9. Animal Testing 

We generally recommend that you conduct a pre-clinical animal model
evaluation to evaluate these devices to show that you have adequately
addressed the risks identified in this guidance document. For new device
design features affecting the embolic agent itself (e.g., coatings to
coils, coil structural design, coil materials, particle materials,
particle shape, sizes), the mechanism of detachment, or the catheter
itself, we recommend that the animal study evaluate:

-   ease of delivery (friction and tortuosity)

-   rupture or puncture of the blood vessels

-   recanalization of the vessels/durability of occlusion

-   local and systemic foreign body reactions

-   device migration

-   embolization effectiveness.

Because changes in embolization agent design and materials of
construction may influence the healing process of the embolization site,
we recommend that you perform follow-up evaluations with appropriate
frequency and after sufficient time has passed to evaluate acute as well
as chronic toxicity. We also recommend that you provide an explanation
of how the animal model relates to the human condition through any
pertinent literature references and/or supporting testing.

# 10. Clinical Testing 

In accordance with the least burdensome provisions of the FDA
Modernization Act of 1997, FDA will rely upon well-designed bench and/or
animal testing rather than requiring clinical studies for new devices
unless there is a specific justification for asking for clinical
information to support a determination of substantial equivalence.
While, in general, clinical studies will not be needed for most vascular
or neurovascular embolization devices, FDA may recommend that you
collect clinical data for a vascular or neurovascular embolization
device with:

-   designs or material formulations (e.g., coatings to coils, coil
    structural design, coil materials, particle materials, particle
    shape, sizes, mechanism of detachment, novel catheter design)
    dissimilar from designs or material formulations used in legally
    marketed devices of the same type

-   new technology, i.e., technology different from that used in legally
    marketed devices of the same type

-   indications for use dissimilar from devices of the same type.

Vascular and neurovascular embolization devices are classified as
different generic types of devices, thus FDA does not consider them to
be "of the same type" in the criteria described above.

FDA will always consider alternatives to clinical testing when the
proposed alternatives are supported by an adequate scientific rationale.
The review branches identified on the cover of this guidance document
are available to discuss any clinical testing with you before you
initiate your studies.

If a clinical study is needed to demonstrate substantial equivalence
(i.e., 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. FDA believes that the vascular and
neurovascular embolization devices addressed by this guidance document
are significant risk devices as defined in 21 CFR § 812.3(m).[^4] In
addition to the requirement of having an FDA-approved IDE, sponsors of
such trials must comply with the regulations governing institutional
review boards (21 CFR Part 56) and informed consent (21 CFR Part 50).

After FDA determines that the device is substantially equivalent,
clinical studies conducted in accordance with the cleared indications,
including clinical design validation studies conducted in accordance
with the quality systems regulation, are exempt from the investigational
device exemptions (IDE) requirements. However, such studies must be
performed in conformance with 21 CFR Part 56 and 21 CFR Part 50.

We recommend that you consider the following information specific to
embolization clinical studies.

> *Endpoints*
>
> We recommend that the study protocol include clearly defined primary
> and secondary endpoints and specific success/fail criteria for the
> study. We recommend that you define and report all adverse events.
>
> We recommend that effectiveness endpoints include the reduction in
> size of the vascular lesion, percentage occlusion of an aneurysm, or
> the occlusion of a parent vessel as measured by angiography. We also
> recommend that you consider other endpoints, such as the
> recanalization rate of the embolized vascular lesion and/or the
> determination of the clinical benefit. For example, for devices used
> for presurgical embolization, a reduction in surgical time and blood
> loss may be appropriate endpoints.
>
> For **neurovascular** embolization devices, we recommend that the
> safety evaluation include:

-   the incidence of new neurological deficits (transient and permanent)

-   grading of neurological deficit status (i.e., did the deficit
    lessen, stay the same, or deteriorate)

-   the rate of neurological and non-neurological complications

-   distal migration of particular material.

> We recommend that you identify the measurement tools used to assess
> patient neurological endpoints. We recommend that you evaluate all
> patients, at a minimum, pre-embolization, immediate post-embolization,
> and at a follow-up examination using a standard neurological
> examination that tests:

-   cranial nerves

-   sensory function

-   motor function and reflexes

-   gait and coordination

-   mentation.

> We recommend that you provide a copy of the neurological examination
> as a case report form on which the clinician will record results.
> Other means of measuring endpoints may include:

-   functional outcome scales

-   patient self-reports

-   clinician or surgeon self-reports (World Federation of Neurosurgeons
    grade (WFNS), Glasgow Outcome Scale (GOS), Glasgow Coma Scale (GCS),
    NIH Stroke Scale, and/or Barthel Index).

> We recommend that the evaluation of endpoints be independent and
> masked. For any scale used, we recommend that the directions for
> determining values in the test be part of the case report form and
> that the scale range be indicated on the case report form where the
> score will be entered. When appropriate, we recommend that you
> consider neuropsychological testing (e.g., personality, associations,
> IQ).
>
> *Description of Embolization Procedure*
>
> We recommend that you provide a full description of the embolization
> procedure in the protocol, including:

-   device/component assembly and preparation

-   use of anticoagulation medication (e.g., drug, dose)

-   use of antibiotics

-   circumstances under which adjunctive embolization devices may be
    used during the procedure

-   whether there is a plan for staged embolization and the features of
    that plan

-   the therapy available in the event of stroke or other complication
    during the embolization procedure

-   the time interval between embolization and definitive resection if
    embolization is a pre-surgical procedure.

> In addition, we recommend that you monitor the neurological function
> during implantation of neurovascular embolization devices in patients
> under local anesthesia.
>
> *Imaging*
>
> Pre-operative imaging procedures are standard of care for patients
> requiring embolization. In addition to pre-operative evaluation,
> post-embolization angiography and short-term and long-term follow-up
> imaging scans may be appropriate when evaluating embolization agents
> with novel design features. We recommend that you describe the methods
> used to measure the lesion (e.g., angiography, MRI, MRA, CT), as well
> as the follow-up intervals. Because the vascular disorder and device
> use may determine which imaging tools are used and the length and
> interval of follow-up, we recommend that you provide the rationale for
> these protocol designs along with any supporting literature/studies.
>
> *Patient Follow-up*
>
> We recommend that you specify how often patients should be evaluated
> during follow-up.

# 11. Labeling

The 510(k) 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).[^5]

> *Prescription Use*
>
> As a prescription device, under 21 CFR § 801.109, the device is exempt
> from having adequate directions for lay use. Nevertheless, under 21
> CFR § 807.87(e), we expect to see clear and concise instructions 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.
>
> *Instructions for Use*
>
> We recommend that the instructions for use include:

-   the minimum and maximum internal diameter of the embolization
    delivery catheter

-   information on any contrast media and flushing agent used with your
    device

-   for a detachable balloon, the pressure required to rupture the
    balloon and the specification for the maximum inflation pressure.

[^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]: Refer to Blue Book Memorandum entitled "SIGNIFICANT RISK AND
    NONSIGNIFICANT RISK MEDICAL DEVICE STUDIES" at
    <http://www.fda.gov/cdrh/d861.html>.

[^5]: Although final labeling is not required for 510(k) clearance,
    final labeling must comply with the requirements of 21 CFR Part 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.