Dear Panel Member:

We seek your recommendation on the appropriate device classification of
the following devices:

Bone Wax

Medical Maggots

Medicinal Leeches

Tissue Expanders &

Wound Dressings with Drugs

To assist in your preparation for the Panel discussion, the following
information is enclosed regarding this topic:

TAB 1 Information describing the classification process for unclassified
devices and slides pertinent to the classification of each of the above
referenced devices

TAB 2 The Bone Wax Device

TAB 3 Medical Maggots

TAB 4 Medicinal Leeches

TAB 5 Tissue Expanders

TAB 6 Wound Dressings with Drugs

TAB 7 Literature Articles pertaining to each device

TAB 8 Classification Topics

TAB 9 Panel Questionnaire

TAB 10 "*Class II Special Controls Guidance Document: Surgical sutures;
Draft Guidance of Industry and FDA"*

TAB 11 "*The Least Burdensome Provisions of the FDA Modernization Act of
1997: Concept and Principles; Final guidance for FDA and Industry"*

If you need additional information or clarification regarding the
information provided in this package, please contact me at 301-594-3090
X132.

LT Ayanna Hill, Project Manager Date

FDA/CDRH/ODE/DGRND/PRSB

**TAB 1**

**MEMORANDUM**

**Date:** July 27, 2005

**To:** General and Plastic Surgery Devices Panel

**From:** Division of General, Restorative, and Neurological Devices
(DGRND) Scientific Reviewers

**Subject:** Classification of the following devices:

Bone Wax

Medical Maggots

Medicinal Leeches

Tissue Expanders &

Topical Wound Dressing that Contain Drugs and/or Biologics

**Summary of Device Regulation and Unclassified Devices:**

Inadvertently a few medical devices were not classified at the time of
the Medical Device Amendments of 1976 (the 1976 Amendments) to the Food,
Drug and Cosmetic Act (the Act) (21 USC 360C). These medical devices are
currently regulated as unclassified devices via pre-market notification
\[510(k)\].

The 1976 Amendments to the Act as amended by the Safe Medical Device Act
(SMDA) of 1990, the FDA Modernization Act (FDAMA) of 1997, and the
Medical Device User Fee Modernization Act (MDUFMA) of 2002 provide
regulations for the classification and regulation of medical devices
intended for human use. FDA is required to classify all medical devices,
including the remaining unclassified medical devices into the lowest
regulatory class that can reasonably assure their safety and
effectiveness for their intended use.

The Act established three categories (classes) of medical devices
depending on the regulatory controls needed to provide reasonable
assurance of their safety and effectiveness. The three classes are Class
I (general controls), Class II (special controls), and Class III
(pre-market approval). General controls are sufficient to provide
reasonable assurance of the safety and effectiveness of Class I devices.
General controls include the following: prohibition against adulterated
or misbranded devices, pre-market notification (510(k)), banned devices,
the quality system regulation that includes design controls and good
manufacturing processes (GMPs), registration of manufacturing
facilities, listing of device types, record keeping, etc. Class II
devices are those that cannot be classified into Class I because general
controls by themselves are insufficient to provide reasonable assurance
of the safety and effectiveness of such devices. These devices are
regulated using special controls and general controls. Special controls
include guidelines (guidance documents), performance standards,
post-market surveillance, clinical data, labeling, tracking
requirements, and other appropriate actions the Secretary of the
Department of Health and Human Services deems necessary to provide such
assurance. Class III devices are those for which insufficient
information exists to determine that general and special controls are
sufficient to provide reasonable assurance of the safety and
effectiveness. These devices are life sustaining, life supporting, or
substantially important in preventing impairment of human health, or
they present unreasonable risk of illness or injury. Class III devices
are regulated by using "valid scientific evidence" to establish the
safety and effectiveness of the device. Valid scientific evidence
includes well-controlled investigations, partially-controlled studies,
uncontrolled studies, well-documented case histories, and reports of
significant human experience.

When most device types were classified in the late 1970s and early
1980s, most Class I and Class II devices were cleared for marketing via
the 510(k) process. Some Class I devices were also exempted from 510(k)
clearance. Now most Class I devices and a few Class II devices are
exempt from 510(k) clearance because their safety and effectiveness can
be reasonably assured by other general controls, particularly by the
quality system regulation general control. Examples of class I exempt
products include surgical apparel, nonabsorbable gauze for internal use;
hydrogel wound dressings and manual surgical instruments such as clip
appliers and forceps. Examples of non-exempt Class II devices include
implantable surgical meshes, sutures, implantable clips and staples,
dura mater substitute devices, and chin prosthesis. Examples of Class
III devices include interactive wound dressings, adhesion barriers,
silicone gel-filled breast prostheses and injectable fillers for facial
aesthetic correction.

**Draft Special Controls Guidance Document:**

If the Office of Device Evaluation (ODE) considers classifying a medical
device that was previously unclassified into regulatory Class II, such
classifications are accompanied by what the Agency refers to as a draft
"Special Controls" guidance document that is released for public
comment. In the vast majority of cases, the special control has been in
the form of a guidance document. The guidance document: *"Class II
Special Controls Guidance Document: Surgical sutures; Draft Guidance of
Industry and FDA"*, issued on June 3, 2003, is provided in **TAB 10** as
an example of a Class II special controls guidance document for a
transitional device that was reclassified from Class III to Class II.
The content of a Class II special controls guidance document for any of
the above referenced devices should be very similar to the sample
guidance document provided with the exception that specific device
information would be different.

While the agency has not developed nor provided you with a copy of a
proposed draft special controls guidance document for the above
referenced devices, we are providing memos which includes sections for
guidance documents for your review. At present, a special controls
guidance document may be comprised of up to 12 sections.

**The Least Burdensome Provisions of FDAMA:**

A central purpose of the Food and Drug Administration Modernization Act
of 1997 (FDAMA) is "to ensure the timely availability of safe and
effective new devices that will benefit the public and to ensure that
our Nation continue to lead the world in new device innovation and
development. Congress' goal was to streamline the regulatory process
(i.e., reduce burden) to improve patient access to drugs and devices
that could benefit the public.\
\
One of the concepts central to this "least burdensome" approach to the
regulation of medical devices is to review devices at the Class level
(Class I, Class II, Class III) where they will receive an appropriate
level of oversight in accordance with what is known about the safety and
effectiveness of the device type. Since bone waxes have been in use for
approximately 100 years, the Agency believes that they can be
appropriately regulated at the Class II, Special Controls, regulatory
level because the assessment of their effectiveness and the known
complications are well understood due to the many years of experience in
their use. More than just risk is taken into account when devices are
classified. An understanding of the methods to assess safety and
effectiveness is a central factor in the classification of medical
devices. Other Class II devices that are considered to have high risks
associated with their use are dura replacements, surgical meshes and
sutures.

The Guidance Document: *The Least Burdensome Provisions of the FDA
Modernization Act of 1997: Concept and Principles; Final guidance for
FDA and Industry*, is provided as a reference for your convenience,
located in **TAB 11**.

As described in the Least Burdensome Provisions of the FDA Modernization
Act of 1997: Concept and Principles; Final Guidance for FDA and Industry
([www.fda.gov/cdrh/ode/guidance/1332.pdf](http://www.fda.gov/cdrh/ode/guidance/1332.pdf)
), the purpose of a 510(k) submission is to determine whether the device
is "substantially equivalent." to a predicate device. Section 513(i) of
the act establishes the criteria for determining whether "substantially
equivalent." This section of the act states that FDA may issue an order
of substantial equivalence only if it determines that the device has the
same intended use as a predicate device and is as safe and effective as
a legally marketed device.

> FDA and industry should focus on those issues that can affect the
> substantial equivalence determination, that is, whether the device has
> the same intended use as the predicate device and is as safe and
> effective as a legally marketed device. Information unrelated to the
> substantial equivalence decision should not be submitted to nor
> requested by, the agency. This would normally include information
> related to cost effectiveness, consumer preference testing and
> comparative testing. Information that is scientifically interesting
> but not necessary for the purpose of determining substantial
> equivalence should not be part of the submission.

**TAB 2**

**Bone Wax**

**Brief History and Regulation of Bone Wax:**

In general, bone waxes are medical devices that contain white beeswax as
the major component. Most medical texts assign the invention of bone wax
to two individuals: Rushton Parker, who, in 1892, reported that a
mixture of white beeswax, olive oil and phenol had significant
hemostatic properties when applied to broken bones and Sir Victor
Horsley, who, later that same year, employed the same bone wax recipe to
control bleeding in orthopedic surgical procedures. Most of the bone
waxes in use today are based on the bone wax described and employed by
Parker and Horsley in 1892 and are, for the most part, formulated as
approximately 70% white beeswax and approximately 30% of some type of
softening agent or agents. The hemostatic character of these products is
dependent on the beeswax because it gives the material the ability to
cling to the bone and physically block bleeding. The softening agent is
added to make the beeswax soft and kneadable so that the surgeon may
place it and remove what is not needed in order to maintain a tamponade
effect. The softening agents are most often oils, paraffin waxes,
palmitates and petrolatum.

Bone waxes have been regulated as unclassified medical devices through
the clearance of a pre-market notification \[510(k)\] since the first
one (Lukens Bone Wax) was cleared in 1979. The Lukens Bone Wax had been
marketed since 1904, but they submitted a 510(k) for a sterilization
change. Following the 1979 clearance of the Lukens Bone Wax
(manufactured by Lukens, Inc., cleared via K791495 and formulated from
beeswax, almond oil and salicylic acid), CDRH has cleared five
additional bone waxes: Auto Suture Bone Wax (US Surgical, cleared via
K971680 and formulated from glycolide, caprolactone, mannitol and
β-tricalcium phosphate), Aesculap Bone Wax (Aesculap, Inc., cleared via
K000021 and formulated from beeswax and petroleum jelly), CP Medical
Bone Wax (CP Medical, Inc., cleared via K024372 and formulated from
beeswax, paraffin and isopropyl palmitate), AOC Bone Wax (Ceremed, Inc.,
cleared via K041363 and formulated from a mixture of alkylene oxide
copolymers) and Sharpoint Lukens Bone Wax (Surgical Specialties Corp.,
cleared via K050292 and formulated from beeswax, paraffin and isopropyl
palmitate). There appears to be one additional pre-amendment bone wax
that is still on the market, the Ethicon Bone Wax (Ethicon, Inc.
formulated from beeswax, paraffin and isopropyl palmitate), for which
there is evidence that it has been sold in the US since at least 1942.

Up until recently, bone waxes were understood to be non-absorbable
implant materials that remained inside the body for an extended period
of time and were considered by FDA to be a long-term implant as opposed
to absorbable hemostatic agents, which were absorbed within a few months
following implantation. While bone waxes most probably are eventually
absorbed, the process may take many years. However, with the clearance
of the absorbable US Surgical Bone Wax, the Agency removed that
distinction as the US Surgical Bone Wax is a mixture of absorbable
polymers: glycolide, caprolactone, mannitol and β-tricalcium phosphate,
and is absorbed in a relatively short period of time (months rather than
years). Table 1 identifies the bone waxes that have been cleared to date
or that have pre-market status, gives a brief description of each and
identifies the pre-market notification number and clearance date.

**Table 1**

**Pre-Amendment Bone Waxes and Those Cleared Through Pre-market
Notification \[510(k)\]**

  ------------- ---------------- ---------------- --------------------- ---------------
  **Product**   **Present        **Notification   **Characteristics**   **Clearance
                Application      Number**                               Date**
                Holder**                                                

  **Horsley's   None             Pre-amendment    Beeswax, olive oil,   Invented in
  Wax**                                           phenol                1892

  **Bone Wax**  Ethicon, Inc.    Pre-amendment    Beeswax, paraffin,    Available
                                                  isopropyl palmitate   before 1976

  **Bone Wax**  Lukens, Inc.     Pre-amendment    Beeswax, almond oil,  Available since
                                 and K791495      salicylic acid        1904, 510(k)
                                                                        for
                                                                        sterilization
                                                                        change,
                                                                        September 24,
                                                                        1979

  **Auto Suture US Surgical      K971680          Glycolide,            October 24,
  Bone Wax**    Corp.                             caprolactone,         1997
                                                  mannitol, tricalcium  
                                                  phosphate             

  **Bone Wax**  Aesculap, Inc.   K000021          Beeswax, petroleum    March 27, 2000
                                                  jelly                 

  **Bone Wax**  CP Medical, Inc. K024372          Beeswax, paraffin,    June 19, 2003
                                                  isopropyl palmitate   

  **AOC Bone    Ceremed, Inc.    K041363          Alkylene oxide        July 27, 2004
  Wax**                                           copolymers            

  **Sharpoint   Surgical         K050292          Beeswax, paraffin and March 9, 2005
  Lukens Bone   Specialties                       isopropyl palmitate   
  Wax**         Corp.                                                   
  ------------- ---------------- ---------------- --------------------- ---------------

**Risks to Health**

In order to summarize the potential risks associated with the use of
bone waxes, we reviewed the adverse event reports submitted to the
agency via the Medical Device Reporting (MDR) System, which was
voluntary from 1992 until 1996 when it became mandatory for
manufacturers to report any device failures they were aware of. The MDRs
(up until June 13, 2005) for bone wax received by the Agency are
summarized in Table 2.

**Table 2: Adverse Events Reported**

  ----------------------------------------------- -----------------------
  **Adverse Event**                               **Number of Reports**

  **Granuloma**                                   1

  **Infection**                                   2

  **Paralysis**                                   1

  **Total**                                       4
  ----------------------------------------------- -----------------------

The following literature articles are indicative of the published
literature on bone waxes. These articles discuss bone waxes and also
describe some potential risks of using these devices. Copies of the
following articles are provided in **TAB 7**:

1.  Tan, Tze-Ching and Peter McL. Black. Sir Victor Horsley (1857-1916):
    Pioneer of neurological surgery. Neurosurgery [50]{.underline}(3):
    607-12 (2002).

2.  Schonauer, Claudio, Enrico Tessitore, Giuseppe Barbagallo, Vincenzo
    Albanese and Aldo Moraci. The use of local agents: bone wax,
    gelatin, collagen, oxidized cellulose. European Spine Journal
    [13]{.underline}(Suppl. 1): S89-S96 (2004).

3.  Finn, Maxwell D., Sterling R. Schow, and Emet D. Schneiderman.
    Osseous regeneration in the presence of four common hemostatic
    agents. Journal of Oral and Maxillofacial Surgery [50]{.underline}:
    608-12 (1992).

These articles, as well as others, and bone wax labels were reviewed in
order to compile the risks identified in Table 3. Table 3 also
identifies the methods that will be proposed to ameliorate these risks.

# 

# Table 3: Table of Potential Risks and Controls

  ------------------------------------------ ----------------------------
  **Potential Risk**                         **Control**

  Uncontrolled bleeding due to device        Animal Studies, Clinical
  failure                                    Data

  Infections due to improper sterilization   Animal Studies, Device
  and enhanced bacterial growth              Labeling, QSR, Bench Testing

  Inflammation and/or edema due to foreign   Device Labeling,
  body reaction                              Biocompatibility Testing

  Granuloma formation                        Animal Studies, Device
                                             Labeling

  Failure to be absorbed                     Bench Testing, Animal
                                             Studies

  Reduced strength of methylmethacrylate     Device Labeling
  adhesion when used to attach prosthetic    
  devices to bone surfaces                   

  Use of antiplatelet drug therapy and       Device Labeling
  systemic heparinization may increase risk  
  for device failure                         

  Interference with bone regeneration        Bench Testing, Animal
                                             Studies and Labeling
  ------------------------------------------ ----------------------------

FDA believes that the risks to health identified in Table 3 may be
controlled by use of special controls, i.e., a guidance document that
outlines the testing and studies that should be performed in order to
ameliorate these risks.

**Proposed Identification for Bone Wax for the Code of Federal
Regulations:**

*Identification*. A bone wax is a bone adherent material used to control
bleeding from bone via the physical mechanism of tamponade.

**Rationale for Proposed Class II Regulatory Status for Bone Wax:**

The Agency's rationale for suggesting that this device be classified
into Class II is summarized as follows:

-   We have years of experience regulating these devices (since 1979)

-   We understand the device specifications and performance
    characteristics (bench testing, animal testing and clinical data)
    needed to evaluate and control their safe and effective use.

-   Classification to Class II meets the FDA mandate to apply the "least
    burdensome" approach to regulating medical devices.

The Agency's rationale for identifying a Class II designation as
appropriate is based on the long history of safe and effective use of
these devices over the past 100 years and the scarcity of adverse event
reports in the medical literature and the FDA's Medical Device Reporting
System. The Agency proposes that all of the potential risks to health
can be ameliorated via a special controls guidance document that
includes recommendations and advice on device materials, device
performance, animal testing, clinical testing, device sterilization,
biocompatibility and device labeling.

The recent MDUFMA amendment to the FD&C Act directed the Agency to
regulate medical devices in the "least burdensome" manner possible based
on the available safety and effectiveness information. Please keep this
in mind as you consider classification of these devices. A copy of the
least burdensome guidance document is included in **TAB 11**.

FDA proposes that the bone waxes can be regulated with special controls.
Following are the relevant draft sections of a proposed bone wax
guidance document for your consideration as you discuss the appropriate
classification for this device.

For a proposed absorbable surgical hemostatic agent devices special
control document, sections 1 through 4 and 9 through 11 should be mostly
boilerplate language except for references to the device type and
regulation numbers. For your information and review we are providing
some suggestions for the content being considered for inclusion in
Sections 5 through 8 of a proposed special controls guidance document
for bone waxes. Please note that the information presented in this
memorandum is suggested content and, therefore, the exact format and
information contained in any draft special controls guidance document is
subject to change.

**Suggested Content for Sections 5 through 8**

**Section 5-Risks to Health**

> This section would include information quite similar to the table
> above, which discusses the risks to health associated with the use of
> bone waxes. The information to be placed in that chapter is proposed
> as follows:
>
> In the table below, FDA has identified the risks to health generally
> associated with the use of bone waxes. The measures recommended to
> mitigate these identified risks are given in this guidance document,
> as shown in the table below. You should also conduct a risk analysis,
> prior to submitting your 510(k), to identify any other risks specific
> to your device. 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, you should provide sufficient detail to
> support the approach you have used to address that risk.

  -----------------------------------------------------------------------
  **Identified risk**               **Recommended mitigation measures**
  --------------------------------- -------------------------------------
  Uncontrolled bleeding due to      Guidance document sections on:
  device failure                    Material and Performance
                                    Characteristics, Animal Testing,
                                    Clinical Data and Labeling

  Infection due improper            Guidance Document Sections on: Animal
  sterilization and enhanced        Testing, Sterility, and Labeling
  bacterial growth                  

  Inflammation and Edema due to     Guidance Document Sections on: Animal
  foreign body reactions            Testing, Biocompatibility and
                                    Labeling

  Granuloma formation               Guidance Document Sections on: Animal
                                    Testing and Labeling

  Failure to be absorbed            Guidance Document Sections: Material
                                    and Performance Characteristics,
                                    Animal Testing and Biocompatibility

  Reduced strength of               Guidance Document Section on: Device
  methylmethacrylate adhesion when  Labeling
  used to attach prosthetic devices 
  to bone surfaces                  

  Antiplatelet drug therapy and     Guidance Document Section on: Device
  heparinization may increase risk  Labeling
  for device failure                

  Interference with bone            Guidance Document Sections on: Bench
  regeneration                      Testing, Animal Studies and Labeling
  -----------------------------------------------------------------------

**Section 6-Material and Performance Characterization:**

> This section would include the types of bench top testing, material
> characterization and manufacturing information that the Agency would
> be looking for. The proposed chapter would read as follows:
>
> We recommend that you provide the information below to establish the
> material and performance characteristics of the device.
>
> **Material Specification**
>
> We recommend that you provide all material components of the device.
> Such information should identify the source and purity of each
> component. Such information may also be supplied by reference to a
> Master Access File(s), if the appropriate letter of cross reference is
> included. Submission of a Certificate(s) of Analysis (CoA) and/or a
> Materials Safety Data Sheet(s) (MSDS) can also greatly simplify FDA's
> review of components/materials.
>
> **Product Characterization**
>
> We recommend that the product manufacturing process be briefly
> described and compared to that of the legally marketed predicate
> device.

We recommend that you provide the following product characterization
information regarding your bone wax:

-   a complete description of all components and amounts of components,

-   the time to complete device resorption determined in animal studies,
    and

-   a profile of the ability of the device to adhere to bone and form a
    tamponade.

**Final Product Specification**

> We recommend that you provide information about the relevant
> in-process and final product tests, including identification of the
> test method and time of testing during manufacture and the final
> product release specifications.
>
> Examples of final product release specifications include:

-   specific melting temperature

-   residual levels of manufacturing reagents

-   residual levels of heavy metals

-   pyrogen levels

-   sterility

> We also recommend that you provide the rate of product absorption.
> Such studies should be performed *in vivo* or in a manner expected to
> accurately predict product decomposition (e.g., in comparable cellular
> and proteolytic environments at 37°C). Please see Section 7 (**Animal
> Testing**) below for more details regarding this recommendation.
>
> **Shelf Life\
> \
> **We recommend that you provide both stability testing of the device
> and packaging testing to establish the shelf life (i.e., expiration
> date) for the labeling of your bone wax. Accelerated testing should be
> supported/validated by real-time shelf life testing. With regard to
> mechanical testing, we recommend that you provide the data from the
> applicable test(s) described in Section C above on representative aged
> samples. With regard to packaging testing, we recommend that you
> provide data for the final finished package for initial integrity and
> maintenance of integrity after selecting the appropriate materials and
> qualifying the package configuration. We recommend that you use test
> methods that are either validated or standardized.

**Section 7-Animal Testing**

> This chapter discusses the animal testing the Agency would recommend.
> The information proposed for inclusion into this chapter is as
> follows:
>
> FDA recommends that you provide animal testing that models each
> surgical application for which your device is to be indicated. For
> example, for control of bleeding from bone, we recommend that the
> animal testing include specific bone bleeding models that assess the
> ability of the bone wax to adhere to the bone and that assess the time
> to complete hemostasis.\
> \
> FDA recommends that your animal study evaluate the time to hemostasis,
> time to resorption of the bone wax, the ability of the bone wax to
> adhere to bone, and any complications. We recommend that you monitor
> complications, such as infection, hematoma, coagulopathies, increased
> wound healing time, etc.\
> \
> FDA also recommends that your animal study include testing of a
> legally marketed predicate device of similar components and
> manufacture so that observations can be made as to the substantial
> equivalence of the two devices in reference to the evaluations
> outlined in the paragraph above.\
> \
> The extent of animal testing needed will be dependent upon the
> differences between the proposed device and a legally marketed
> predicate device.

**Section 8-Clinical Testing:**

> This chapter of the special controls guidance document discusses
> clinical data. The information proposed for this chapter is as
> follows:

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 bone
waxes, FDA may recommend that you collect clinical data for a bone wax
with:

-   new technology (i.e., technology different from that used in a
    legally marketed bone wax); or

-   new indications for use for a bone wax of the same type.

FDA will always consider alternatives to clinical testing when the
proposed alternatives are supported by an adequate scientific rationale.
Please contact the Plastic and Reconstructive Surgery Devices Branch
(PRSB) to discuss any clinical testing before initiating 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 812.
>
> After FDA determines that the device is substantially equivalent,
> clinical studies conducted in accordance with the indications reviewed
> in the 510(k), 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 56 and 21 CFR 50.
>
> []{.mark}
>
> Some additional clinical study information specific to bone wax is
> provided below. If you have questions about protocol design not
> addressed in this guidance document, you are encouraged to contact the
> Plastic and Reconstructive Surgery Devices Branch.
>
> Bone waxes are primarily applied during orthopedic surgical procedures
> or bone trauma treatment procedures in order to control bleeding from
> bones. Accordingly, a clinical study should address the following:

-   The study should be a controlled, prospective, randomized clinical
    investigation where the subject bone wax is compared to a legally
    marketed predicate device. In most cases, such comparisons should be
    made between bone waxes manufactured from similar materials and with
    similar indications for use.

-   The study should be conducted at an adequate number of institutions
    to assure that the product performance will be acceptable with
    potential technical and procedural differences encountered when the
    product is marketed.

-   Patients should be followed for the amount of time required for
    complete healing of the bone injured or surgically repaired or for
    two months, whichever is longer. Relevant blood work should be
    performed before and after application of the device. In some cases,
    when a combination of more than one hemostatic product (i.e.,
    absorbable hemostatic agent, bone wax and thrombin) is employed,
    antibody formation may need to be assessed at the time when antibody
    production would reach its maximum level (approximately 4 to 6 weeks
    after exposure to the combination of hemostatic devices).

-   Patients with both traumatic orthopedic surgical repairs and planned
    orthopedic procedures should be enrolled.

-   For any specialized use of bone wax, beyond the standard bleeding
    from bone indication, we recommend that you collect additional
    safety and effectiveness data.

-   The primary effectiveness endpoint for the clinical study should be
    either (1) time to complete hemostasis or (2) hemostasis within a
    specified time limit -- yes/no.

-   The primary safety endpoints should be a full evaluation of all
    adverse events observed during the administration of the device and
    recovery period from surgery until the patient exits the study.

-   Additionally, data on the ability of the bone wax to adhere to the
    bone should be collected.

David Krause, PhD, Expert Biologist Date

Plastic & Reconstructive Surgery Devices Branch

Division of General, Restorative & Neurological Devices

**TAB 3**

**Medical Maggots**

**[Device Definition]{.underline}**

FDA is proposing the following identification for Medical Maggots:

> Medical Maggots are blow fly (i.e., Phaenicia Sericata) larvae
> intended for debriding non-healing necrotic skin and soft tissue
> wounds, including pressure ulcers, venous stasis ulcers, neuropathic
> foot ulcers and non-healing traumatic or post-surgical wounds

**[Device Summary and Intended Use/Indications:]{.underline}**

# Extract from the History of Maggot Therapy (http://www.larve.com/maggot_manual/docs/history.html)

## "Maggot therapy in ancient times"

The primitive, carrion-breeding habit of blowflies has been known and
recorded for centuries. A very early reference can be found in the
*Hortus Sanitatus*, one of the earliest European medical texts,
published at Mainz in 1491.

In contrast, there are some indications that some primitive societies
have recognized that the larvae of certain flies can have beneficial
effects upon the healing of infected wounds. In the early part of this
century, the Ngemba tribe of New South Wales, Australia, commonly used
maggots to cleanse suppurating or gangrenous wounds and it is said that
the aborigines traced this practice back to their remote ancestors^1,2^.
The Hill Peoples of Northern Burma were observed during World War II
placing maggots on a wound then covering them with mud and wet grass:
the Mayans of Central America ceremoniously exposed dressings of beef
blood to the sun before applying them to certain superficial tumors;
after a few days the dressings were expected to pulsate with
maggots^2,\ 3^.

## Maggots in military conflicts

The opportunistic infestation of wounds, particularly those sustained in
battle, has similarly been observed throughout the centuries. Ambroise
Paré (1509-1590), Chief Surgeon to Charles IX and Henri III, recorded
that in the battle of St. Quentin (1557) maggots frequently infested
suppurating wounds^4^.

Napoleon\'s Surgeon in Chief, Baron Dominic Larrey, quoted by
Goldstein^4^ reported that when maggots developed in battle injuries,
they prevented the development of infection and accelerated healing.
\`*These insects, so far from being injurious to their wounds, promoted
rather their cicatrization by cutting short the process of nature and
causing the separation of cellular eschars which they devoured. These
larvae are indeed greedy only after putrefying substances and never
touched the parts endowed with life*\'. There is no evidence, however,
that Larrey deliberately introduced maggots into his patients\' wounds.

During the American Civil War, a Confederate medical officer Joseph
Jones, quoted by Chernin^5^ noted the beneficial effects of wound
myiasis as follows; \`*I have frequently seen neglected wounds filled
with maggots, as far as my experience extends, these worms only destroy
dead tissues, and do not injure specifically the well parts. I have
heard surgeons affirm that a gangrenous wound which has been thoroughly
cleansed by maggots heals more rapidly than if it had been left to
itself*.\'

According to Baer^6^ and McLellan^7^ the Confederate surgeon J.
Zacharias, may have been the first western physician to intentionally
introduce maggots into wounds for the purpose of cleaning or debriding
the wound. Baer quotes Zacharias as stating: \`*During my service in the
hospital in Danville, Virginia, I first used maggots to remove the
decayed tissue in hospital gangrene and with eminent satisfaction. In a
single day would clean a wound much better than any agents we had at our
command\.... I am sure I saved many lives by their use, escaped
septicaemia, and had rapid recoveries*\'

A fascinating review of the early history of maggots in wound care was
published in 1932 by Goldstein^8^.

## Maggot therapy in the early 20^th^ century

The founder of modern maggot therapy is William Baer (1872-1931),
Clinical Professor of Orthopaedic Surgery at the Johns Hopkins School of
Medicine in Maryland^6^.

He described how, during the First World War, he had treated two wounded
soldiers who had remained overlooked on the battlefield for seven days
having sustained compound fractures of the femur and large flesh wounds
of the abdomen and scrotum. On arrival at the hospital they showed no
sign of fever or septicaemia despite the very serious nature of their
injuries and their prolonged exposure to the elements without food or
water. On removal of their clothing Baer *found \`thousands and
thousands of maggots that filled the entire wounded area*.\' To Baer\'s
surprise, when these were removed *\`there was practically no bare bone
to be seen and the internal structure of the wounded bone as well as the
surrounding parts was entirely covered with most beautiful pink
granulation tissue that one could imagine*\'. This at a time when the
mortality rate for compound fractures of the femur was about 75-80%.
Support for Baer\'s observations was provided by Crile & Martin^9^ who
also reported that soldiers whose wounds were infested with maggots did
far better than their wounded comrades who wounds were not similarly
afflicted.

Following these wartime experiences, Baer treated four children with
intractable bone infections (osteomyelitis) at the Children\'s Hospital
in Baltimore in 1928^6^. His initial use of unsterilized maggots was
very successful and the wounds healed within six weeks. Encouraged by
these results, Baer began to use the technique more widely, but
unfortunately several of his patients developed tetanus and he concluded
that it would be necessary to use sterile maggots for future work.

## The importance of sterility

Having once accepted the importance of using larvae that were free from
microorganisms, Baer devoted some considerable efforts to developing a
suitable sterilization process^6^. He initially attempted to sterilize
maggots themselves by first exposing them to full strength hydrogen
peroxide for two hours, and then immersing them in mercuric chloride
solution 1 in 1000. Although he was able to demonstrate that this
process effectively sterilized the outer surface of the larvae, viable
bacteria persisted within their gut. He then decided to sterilize the
eggs, believing correctly that the contents were sterile. He tried many
different solutions including mercuric chloride, phenol, alcohol,
Mercurochrome, gentian violet, hexylresorcinol and silver nitrate. These
efforts were more successful at achieving sterility, but most also
proved lethal to the eggs. Eventually a technique was developed which
involved the use a solution containing mercuric chloride 1 in 1000, 25%
alcohol and 0.5% hydrochloric acid.

Because of the popularity of maggot therapy in the 1930s, numerous
papers were published describing techniques for breeding flies^10,11^
and producing sterile maggots.

Although Livingston^11^ and Weil\'s group^3^ claimed some success with
the sterilization of hatched larvae, the latter with a solution of
iodine, most centers adopted Baer approach and concentrated on
developing methods for sterilizing the eggs^3,\ 6,10,12,13^. A commonly
used method began with pretreatment in Dakin\'s solution (dilute sodium
hypochlorite, or bleach) followed by immersion in mercuric chloride or
formaldehyde. Simmons^14^ reported satisfactory sterilization using 5%
formalin, 1% sodium hydroxide; yet, even his method did not kill all
spore forming bacteria such as *Cl. perfringens* or *Cl. tetanii*.

## First commercial production of maggots

In the absence of any equally effective alternative for the treatment of
osteomyelitis or infected soft tissue injuries, the use of maggots
spread quickly during the 1930\'s. In the USA, *Lucilia sericata* larvae
were produced by Lederle Corporation^15^ and sold for \$5 per 1000 (now
equivalent to about \$100).

In the mid-1930s, Robinson surveyed 947 North American surgeons known to
have employed maggot therapy^16^. Of the 605 responding surgeons who had
treated 5750 patients, 91.2 % expressed a favorable opinion; only 4.4%
expressed an unfavorable view. The most common complaints raised by
surveyed practitioners were the cost of the maggots, the time and effort
required to construct the maggot dressings, and the degree of discomfort
suffered by patients. Robinson\'s paper also included a list of 54
papers on maggot therapy that had been published by that time.

Other than Baer\'s cases of tetanus and one case of erysipelas, thought
to be associated with the use of non-sterile larvae^3^ no other serious
adverse reactions were reported.

During the 1930s, attempts to isolate the \`maggot active principle\'
led to the use of a topical application of maggot extract to promote
wound debridement and disinfection. Livingston^17^ described the
treatment of 567 patients using maggot therapy alone or in combination
with \`maggot active principle\' derived from *Lucilia sericata*. He
also used a polyvalent vaccine of pyogenic organisms suspended in the
maggot principle as a vehicle administered intra-muscularly. Using this
technique they claimed a success rate of 88%, 38% higher than control
cases treated by other methods. Perhaps not surprisingly, this was
associated with significant systemic reactions, and eventually
abandoned.

## The demise of maggot therapy

These years also marked the beginning of the antibiotic era. By 1940,
sulfonamides already were available, and Chain *et al.^18^* had
discovered the methods for mass-producing Flemming's penicillin. As a
result, by the mid-1940s, maggot therapy had virtually ceased, except as
a treatment of last resort^19,20^ due largely to the ready availability
of the new wonder drug and general improvements in surgical and wound
management techniques.

## 

## Early evidence for the effectiveness of maggot therapy

The early maggot therapy literature contains many references to the
successful treatment of chronic or acutely infected soft tissue
injuries, including those infected with *Clostridium welchii* (*Cl.
perfringens*) the \`gas bacillus\'. Wounds treated with maggots included
abscesses^3^ carbuncles^21^ leg ulcers^22^ pressure ulcers,
mastoiditis^19^ and compound fractures^21^.

Maggots were primarily used, however, in the treatment of osteomyelitis,
^3,6,7,11-13,21-24^ and although unable to digest or liquefy dead bone
(sequestra) they were said to facilitate its separation at the interface
with normal bone, leaving behind clean healthy granulation tissue^3^.
Very many dramatic accounts of its use appear in the literature
summarized by Pomerantz^25^ who stated that following maggot therapy
\`*the end product approximates more closely to normal bone structure
than any of the hitherto accepted methods of treatment*\'

It was also claimed repeatedly that in addition to removing devitalized
tissue, the application of maggots had a positive effect upon the speed
of wound healing. This was first noted by Larrey in 1829 who reported
that when maggots developed in wounds sustained in battle, they
prevented the development of infection and accelerated healing^26^. This
view was also shared by Baer^6^ and Fine^21^ who stated *that \`Maggots
produce rapid and thorough debridement and stimulate granulation tissue
production*\' He was so convinced of their ability in this area that he
stated *that \`when debridement is complete, fewer maggots are used and
their function at this time is to complete to keep the wound clean and
promote healing*\'.

Weil et al.^3^ the first to coin the term \`Larval Therapy\' also
asserted that; *\`Coincident with the removal of necrotic and
devitalized soft structures, is the development of highly vascular
granulation tissue which excretes abundant serum and which may be looked
upon as a very beneficial factor in wound defense in this form of
therapy. \... The apposition of wound margins following larval therapy
brings about a rapid development of granulation tissue, which can often
be noted within a few hours\'*.

Maggots appear to have another interesting and potentially very valuable
ability. They are able to destroy unhealthy or abnormal tissue leaving
healthy tissue in its place. Weil et al.^3^ observed, *\`when the larvae
come into contact with exuberant and edematous granulations, they attack
it vigorously, and remove it as any other abnormal structure, after
which the change to healthy granulation tissue soon occurs. We have
observed that the larvae will attack almost any type of abnormal viable
structure, including malignant tissue as well as devitalized soft or
bony tissues*\'.

This they illustrated by reference to two cases of inoperable breast
cancer and two sarcomas of the thigh. *\`On admission, each breast ulcer
measured the approximate size of half a dollar with the malignant tissue
presenting itself upon a level with the surrounding skin. There was
extensive invasion of almost the entire breast substance. Following four
implantation of larvae in one case there was observed an excavation of
the underlying malignant tissues for a depth of 3.5-4 cm but with only
slight variation in the size of the original skin opening. As the larvae
cleared away the malignant tissue, clean healthy granulation tissue
appeared, the odor disappeared and the wound attempted to close\'*. The
remaining cases showed a similar response and the authors concluded that
malignant tissue has a very weak defense against the activity of larvae.

Subsequently, Bunkis et al.^27^ and Reames et al.^28^ described the
benefits of debridement and odor control resulting from accidental
myiasis of head and neck tumors, and Seaquist and colleagues^29^ also
reported benefits from naturally occurring *Phormia regina* myiasis in a
malignant lesion. This infestation, however, was accompanied by pain.

## Methods of application

Over the years, numerous techniques and dressing systems have been
described for ensuring that maggots are contained within the area of the
wound but many were difficult to construct and almost certainly very
uncomfortable to wear. They typically consisted of layers of crinoline
or gauze^21^ but Child et al., used a piece of 80 mesh brass net set in
a foam frame secured to the skin^12^. Others including Weil^3^ and
Mckeever^30^ adopted a similar approach using copper mesh or milk
strainer wire held in place with adhesive tape or, sometimes, Unna\'s
Paste - a mixture of zinc oxide, gelatin, glycerin, and water^31^.

Self retaining metal^3^, or glass^30^, devices were developed to hold
wounds open during therapy and these allow drainage of the wound and
providing access to the maggots. Ochsenhirt and Komara^32^, described a
complex technique for intraoral treatment, involving dentures with tubes
through which the larvae were introduced.

As part of the application process, Livingston^11^. recommended exposing
the maggots, once applied, to a bright light in order to drive them deep
into the wound, but this was considered unnecessary by Robinson^33^, who
also emphasized the need to control the number of larvae applied,
proposing that as few as 6 might be sufficient for a finger tip injury
although 500-600 may be required for more extensive wounds

Large quantities of larval enzymes can cause significant excoriation if
they are allowed to run onto unprotected skin around the margin of a
wound. In severe cases this resembles a superficial burn, but like such
an injury, this will rapidly resolve over a few days^34^. Robinson^33^,
who had also encountered this problem, suggested that the surrounding
skin should be covered to protect it from larval secretions and to
eliminate the tickling sensation caused by the maggots\' movements. He
considered that the collodion proposed by Weil et al.^3^ and adhesive
plaster advocated by Child^12^ were not suitable as they tended to
separate from the skin once wet. He suggested that a liquid adhesive
system described by Buchman and Blair^13^ or the Unna\'s paste described
by Jewett^31^ would both be far more satisfactory for this purpose.

## Early problems with maggot therapy

Although no serious side effects were noted following the use of
maggots, a transient pyrexia was of 2-4°F was noted on a number of
occasions by Fine^21^ Weil, ^3^ McLellan^7^ and Buchman^13^ who
suggested that this was due to \`*the opening of chronically infected
lymphatics*\' This invariably subsided upon removal of the maggots.

A more inconvenient problem, then as now, was the unexplained failure of
some applications of maggots to survive on the wound. McKeever^30^
suggested that this could be due to the maggots drowning due to poor
drainage but an alternative explanation is that the pH of the wound is
not suitable for the young larvae. Hobson^35^ showed that secretions of
*Lucilia* larvae contain proteolytic enzymes which function optimally at
pH 8.5. As conditions become progressively more acidic the enzyme
activity is reduced. It is possible, therefore, that in a wound with a
relatively low pH, the enzymes will be unable to breakdown the necrotic
tissue and the maggots will therefore starve to death. Some support for
this theory was provided by Wilson et al.^23^ who showed that larvae do
not survive well in an acid environment.

**References**

1\. Dunbar, G. K. Notes on the Ngemba tribe of the Central Darling River
of Western New South Wales. *Mankind* 1944; **3**: 177\
2. Root-Bernstein, R., Root-Bernstein, M. *Honey, mud, maggots, and
other medical marvels*. 1999 ed. London: Macmillan, 1999.\
3. Weil, G. C., Simon, R. J., Sweadner, W. R. A biological,
bacteriological and clinical study of larval or maggot therapy in the
treatment of acute and chronic pyogenic infections. *American Journal of
Surgery* 1933; **19**: 36-48\
4. Goldstein, H. I. Maggots in the treatment of wound and bone
infections. *Journal of Bone and Joint Surgery* 1931; **13**: 476-478\
5. Chernin, E. Surgical Maggots. *Southern Medical Journal* 1986;
**79**(9): 1143-1145.\
6. Baer, W. S. The treatment of chronic osteomyelitis with the maggot
(larva of the blow fly). *Journal of Bone and Joint Surgery* 1931;
**13**(July): 438-475.\
7. McLellan, N. W. The Maggot treatment of osteomyelitis. *Canadian
Medical Association Journal* 1932; **27**: 256-260.\
8. Goldstein, H. I. Live maggots in the treatment of chronic
osteomyelitis, tuberculous abscesses, discharging wounds, leg ulcers and
discharging inoperable carcinoma. *Internat Clinics* 1932; **4**:
269-282.\
9. Crile, G., Martin, E. Clinical Congress of Surgeons of North America,
\"War Session\". *Journal of the American Medical Association* 1917;
**69**: 1538-1541.\
10. Murdoch, F. F., Smart, T. L. A method of producing sterile blowfly
larvae for surgical use. *United States Naval Medical Bulletin* 1931;
**29**: 406-417.\
11. Livingston, S. K. Maggots in the treatment of chronic osteomyelitis,
infected wounds, and compound fractures. An analysis based on the
treatment of one hundred cases with a preliminary report on the
isolation and use of the active principle. *Surgery, Gynecology and
Obstetrics* 1932; **54**: 702-706.\
12. Child, F. S., Roberts, E. F. The treatment of chronic osteomyelitis
with live maggots. *New York State Journal of Medicine* 1931; **31**:
937-943.\
13. Buchman, J., Blair, J. E. Maggots and their use in the treatment of
chronic osteomyelitis. *Surgery, Gynecology and Obstetrics* 1932;
**55**: 177-190.\
14. Simmons, S. W. Sterilization of blowfly eggs in the culture of
surgical maggots for use in the treatment of pyogenic infections.
*American Journal of Surgery* 1934; **25**: 140-147.\
15. Puckner, W. A. New and nonofficial remedies, surgical
maggots-Lederle. *Journal of the American Medical Association* 1932;
**98**(5): 401.\
16. Robinson, W. Progress of maggot therapy in the United States and
Canada in the treatment of suppurative diseases. *American Journal of
Surgery* 1935; **29**: 67-71.\
17. Livingston, S. K. The therapeutic active principle of maggots with a
description of its clinical application in 567 cases. *Journal of Bone
and Joint Surgery* 1936; **18**: 751-756.\
18. Chain, E., Florey, H. W., Gardner, A. D., Heatley, H. G., Jenning,
M. A., Orr-Ewing, J., et al. Penecillin as a chemotherapeutic agent.
*Lancet* 1940; **2**: 226-228.\
19. Horn, K. L., Cobb, A. H., Gates, G. A. Maggot therapy for subacute
mastoiditis. *Archives of Otolaryngology* 1976; **102**: 377-379.\
20. Teich, S., Myers, R. A. M. Maggot therapy for severe skin
infections. *Southern Medical Journal* 1986; **79**: 1153-1155.\
21. Fine, A., Alexander, H. Maggot therapy - technique and clinical
application. *Journal of Bone and Joint Surgery* 1934; **16**: 572-582.\
22. Ferguson, L. K., McLaughlin, C. W. Maggot Therapy - A rapid method
of removing necrotic tissues. *American Journal of Surgery* 1935;
**29**: 72-84.\
23. Wilson, E. H., Doan, C. A., Miller, D. F. The Baer maggot treatment
of osteomyelitis - Preliminary report of 26 cases. *Journal of the
American Medical Association* 1932; **98**: 1149-1152.\
24. Livingston, S. K., Prince, L. H. The treatment of chronic
osteomyelitis with special reference to the use of the maggot active
principle. *Journal of the American Medical Association* 1932; **98**:
1143-1149.\
25. Pomeranz, M. M. Peculiar regeneration of bone, following maggot
treatment of osteomyelitis. *Radiology* 1932; **19**: 212-214.\
26. Larrey, D. J. *Observations on wounds and their complications by
erysipelas, gangrene and tetanus, Clinique. chirurgucale. 51-52 (Nov.)
1829 translated from the French by E.F. Rivinus. Des vers ou larves de
la mouche bleue, Chez Gabon, Paris,*. Philadelphia: Key, Mielke and
Biddle,, 1832.\
27. Bunkis, M. D., Gherini, S., Walton, R. Maggot therapy revisited.
*Western Journal of Medicine* 1985; **142**: 554-556.\
28. Reames, M. K., Christensen, C., Luce, E. A. The use of maggots in
wound debridement. *Annals of Plastic Surgery* 1988; **21**(4):
388-391.\
29. Seaquist, E. R., Henry, T. R., Cheong, E., Theologides, A. Phormia
regina myiasis in a malignant wound. *Minn Med* 1983; **66**: 409-410.\
30. McKeever, D. C. Maggots in treatment of osteomyelitis. A simple
inexpensive method. *Journal of Bone and Joint Surgery* 1933; **15**:
85-93.\
31. Jewett, E. L. The use of Unna\'s paste in the maggot treatment of
osteomyelitis. *Journal of Bone and Joint Surgery* 1933; **15**:
513-515.\
32. Ochsenhirt, N. C., Komara, M. A. Treatment of osteomyelitis of
mandible by intraoral maggot-therapy. *Journal of Dental Research* 1933;
**13**: 245-246.\
33. Robinson, W. Suggestions to facilitate the use of surgical maggots
in suppurative infections. *American Journal of Surgery* 1934; **25**:
525.\
34. Thomas, S., Jones, M., Shutler, S., Jones, S. Using larvae in modern
wound management. *Journal of Wound Care* 1996; **5**(2): 60-69.\
35. Hobson, R. P. On an enzyme from blowfly larvae. (Lucilia Sericata)
which digests collagen in alkaline solution. *Biochemical Journal* 1931;
**25**: 1458, 1931."

**[Risk to Healths]{.underline}**

FDA currently regulates Medical Maggots as an unclassified medical
device. FDA cleared one pre-market notification (510(k)) application for
Medical Maggots devices. We searched medical device reports for
device-related adverse events and found no adverse events reported.

The following literature articles are indicative of the published
literature on Medical Maggots. These articles also describe some
potential risks of using these devices. They are provided in this
package under **TAB 7**.

-   RA Sherman, MJR Hall, S Thomas, "[Medicinal Maggots: An Ancient
    Remedy for Some Contemporary
    Afflictions](http://scholar.google.com/url?sa=U&q=http://ento.annualreviews.org/cgi/reprint/45/1/55),"
    *Ann. Rev. of Entomol*., 2000, **45**, 55 -- 81

-   G. N. Jukema, A. G. Menon, A. T. Bernards, P. Steenvoorde, A. Taheri
    Rastegar, and J. T. van Dissel, "Amputation-Sparing Treatment by
    Nature: \"Surgical\" Maggots Revisited", *Clinical Infectious
    Diseases*, volume 35 (2002), pages 1566--1571

-   K.Y. Mumcuoglu, "Clinical Applications for Maggots in Wound Care"
    [*American Journal of Clinical
    Dermatology*](http://www.ingentaconnect.com/content/adis/derm), 1
    April 2001, **vol. 2**, no. 4, pp. 219-227(9)

In the table below, the risks to health generally associated with the
use of the Medical Maggots are identified. The measures recommended to
mitigate these identified risks are also shown in the table below.

+-----------------------------------+----------------------------------+
| ### Identified Risk               | **Recommended Mitigation         |
|                                   | Measures**                       |
+-----------------------------------+----------------------------------+
| **Adverse tissue reactions**      | Biocompatibility                 |
|                                   |                                  |
|                                   | Device Manufacture               |
|                                   |                                  |
|                                   | Clinical Data                    |
|                                   |                                  |
|                                   | Labeling                         |
+-----------------------------------+----------------------------------+
| **Infection**                     | Sterility and Disinfection       |
|                                   |                                  |
|                                   | Device Manufacture               |
|                                   |                                  |
|                                   | Animal Derived Components        |
|                                   |                                  |
|                                   | Clinical Data                    |
|                                   |                                  |
|                                   | Labeling                         |
+-----------------------------------+----------------------------------+

As stated earlier, this unclassified device will be classified into
Class II which will be subject to special controls.

**[Special Controls Guidance Document:]{.underline}**

For a proposed Medical Maggots document, sections 1 through 4 should be
mostly boilerplate language except for references to the device type and
regulation numbers. For your information and review we are providing
some suggestions for the content being considered for inclusion in
Sections 5 through 12 of a proposed special controls guidance document
for Medical Maggots. Please note that the information presented in this
memorandum is suggested content and, therefore, the exact format and
information contained in any draft special controls guidance document is
subject to change.

**Suggested Content for Sections 5-12**

# Section 5-Device Description

We recommend that you provide the following device description
information:

> We recommend that you identify your device, by the regulation and
> product code described in section **4. Scope** and we recommend that
> you provide the following device description information:

-   A description of the genus and species of the proposed product.

-   The methods for packaging and transport of the Medical Maggots to
    insure viability.

-   Identification of any other patient contact material such as wound
    dressings or pouches used to retain the Medical Maggots at the site
    of application.

-   A description of the storage conditions and time (between shipping
    and device use) that are known to result in safe and effective
    product use.

# 

# Section 6-Risks to Health

This section should include information quite similar to the table
above, which discusses the risks to health associated with the use of
Medical Maggots. The information to be placed in that chapter is
proposed as follows:

> In the table below, FDA has identified the risks to health generally
> associated with the use of the Medical Maggots addressed in this
> document. The measures recommended to mitigate these identified risks
> are given in this guidance document, as shown in the table below. You
> should also conduct a risk analysis, before submitting your 510(k), to
> identify any other risks specific to your device. 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, you should
> provide sufficient detail to support the approach you have used to
> address that risk.

+-----------------------------------+----------------------------------+
| ### Identified Risk               | **Recommended Mitigation         |
|                                   | Measures**                       |
+-----------------------------------+----------------------------------+
| **Adverse tissue reactions**      | Section 7: Biocompatibility      |
|                                   |                                  |
|                                   | Section 9: Device Manufacture    |
|                                   |                                  |
|                                   | Section 11: Clinical Data        |
|                                   |                                  |
|                                   | Section 12: Labeling             |
+-----------------------------------+----------------------------------+
| **Infection**                     | Section 8: Sterility and         |
|                                   | Disinfection                     |
|                                   |                                  |
|                                   | Section 9: Device Manufacture    |
|                                   |                                  |
|                                   | Section10: Animal Derived        |
|                                   | Components                       |
|                                   |                                  |
|                                   | Section 11: Clinical Data        |
|                                   |                                  |
|                                   | Section 12: Labeling             |
+-----------------------------------+----------------------------------+

# Section 7-Biocompatibility

This section discusses the biocompatibility testing FDA would recommend.
The information proposed for inclusion into this chapter is as follows:

> Depending on the methods of product manufacture and other
> patient-contacting materials in the final product (residual
> antibiotics, wound dressing accessories), FDA recommends that you
> consider conducting biocompatibility testing recommended in the
> FDA-modified **Use of International Standard ISO-10993, Biological
> Evaluation of Medical Devices Part-1: Evaluation and Testing.** We
> recommend that testing be conducted on extracts of the final
> product(s) ready for patient administration. Because Medical Maggots
> will be in contact with breached skin for less than 30 days, we
> recommend that the following tests be evaluated:

-   cytotoxicity

-   sensitization

-   irritation or intracutaneous reactivity

# Section 8-Sterility and Disinfection

This section discusses the information concerning sterilization and
disinfection that FDA would recommend be included in the application.
The information proposed for inclusion into this chapter is as follows:

> As a living organism, Medical Maggots cannot be sterilized. However,
> if other device components (e.g., wound dressings or shipping
> containers) undergo sterilization, the following information should be
> provided:
>
> 1\. The method of sterilization;
>
> 2\. The validation method for the sterilization cycle;
>
> 3\. The sterility assurance level (SAL) to be achieved; and
>
> 4\. The method for monitoring the sterility of each production lot.
>
> For addition guidance, review of **510(k) Sterility Review Guidance
> K90-1; Final Guidance for Industry and FDA**,
> (<http://www.fda.gov/cdrh/ode/guidance/361.html>) is recommended.
>
> Methods used to remove or kill microorganisms on the surface of fly
> eggs should be described. Such information should identify the
> effectiveness of the disinfection procedure (i.e., via aerobic and
> anaerobic cultures of disinfected eggs) as well as the resulting
> viability of eggs after treatment. The results of testing assessing
> the level of residual disinfectant(s) present in the final product
> should also be presented.

# Section 9-Device Manufacture

This section discusses the information concerning device manufacture
that FDA would recommend be incldued in the application. The information
proposed for inclusion into this chapter is as follows:

> The application should contain information about all reagents and
> processing steps used in device manufacture. Information about the
> source and purity of reagents (e.g., CoA and/or MSDS) can be very
> helpful in evaluating the substantial equivalence of proposed and
> legally marketed devices.
>
> Information should also be provided for the methods of manufacturing
> any ancillary wound dressings or pouches used to maintain the devices
> at their initial site of patient application.

# Section 10-Animal Derived Material

This section discusses the information and testing related to
animal-derived material that FDA would recommend be incldued in the
application. The information proposed for inclusion into this section is
as follows:

> Because growth and maintenance of Medical Maggots may require feeding
> with animal tissue, information for each animal reagent used should be
> fully described in a 510(k) application or by reference to other
> regulatory submissions (e.g., Master File, PMA, 510(k)), when a letter
> of cross reference is provided. For each animal tissue, regulatory
> applications and facility records should describe the following test
> methods and results:
>
> **Control of Animal Tissue Collection**

-   Animal species

-   Specific tissue(s) used

-   Animal country of origin and residence (more specific geographic
    location when appropriate)

-   Methods for monitoring the health of herd and the health of the
    specific animals from which tissue are collected (including herd
    vaccinations such as live modified viruses that can co-purify in the
    desired tissue)

-   USDA status of the abattoir

-   Methods and conditions for transporting animal tissue

-   Procedures for maintaining records on the above cited issues should
    be presented in regulatory submissions

-   Records of the corresponding test results for each lot of material
    should be maintained at the manufacturing facility or submitted in
    regulatory documents when appropriate

> **Manufacturing Controls for Animal Tissue Components**

-   Test methods and release criteria permitting animal tissues to be
    further processed and/or combined with other animal tissue or device
    components for device manufacture

-   Quaratine procedures for tissues that have not met the release
    criteria

-   Test methods and acceptance criteria for assessing in-process and
    final product bioburden/sterility

-   Methods for facility decontamination/sterilization so that
    cross-contamination is avoided

-   Procedures for maintaining records of the above cited issues should
    be provided in regulatory submissions

-   Records of the corresponding test results for each lot of material
    should be maintained at the manufacturing facility or submitted in
    regulatory documents when appropriate

> **Eliminating Viral Contaminates**
>
> The 510(k) should document all appropriate methods for eliminating
> human infectious agents from the animal tissue used in device
> production. This may include when appropriate, evaluating the ability
> of processing methods and disinfection techniques to inactivate and
> remove viruses.
>
> Such data may be obtained by determining the amount of virus in the
> unprocessed source material and the viral inactivation properties of
> scaled down versions of the specific production and sterilization
> methods (e.g., acid extraction of collagen or dry heat sterilization)
> using appropriate model viruses. The results of these studies should
> demonstrate that the sum of the log clearance of virus from the
> selected processing steps and sterilization processes are at least six
> logs greater than the concentration of virus anticipated in the
> unprocessed source material.
>
> In addition, if bovine material derived from a country in which Bovine
> Spongiform Encephalopathy (BSE) has been observed or a country which
> presents a significant risk of BSE (See 9 CFR § 94.18), the
> application should include a certification that the herd is not
> infected with (BSE). This certification may require information such
> as a herd history, descriptions of the methods use to isolate the
> herd, including the sources of breeding stock, the control of feeds,
> the disposition of animals with central nervous system signs, and
> testing for the BSE agent. Certification that the material was not
> processed using equipment contaminated by animal materials from other
> herds may also be requested.

# Section 11-Clinical Data

This chapter discusses the related to clinical experience that FDA would
recommend be incldued in the application. The information proposed for
inclusion into this chapter is as follows:

> The application should provide a summary of any clinical experience
> obtained with the device. Reference to the appropriate 510(k), PMA or
> IDE number (or cited as overseas experience) may greatly simplify the
> review process when appropriate letters of cross-reference are
> included in the application.

# Section 12-Labeling

This chapter discusses the information and testing related to product
labeling that FDA would recommend be incldued in the application. The
information proposed for inclusion into this chapter is as follows:

The pre-market 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 Part 801.

> **Directions for 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 recommend submitting 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]{.underline}:**
>
> The instructions should describe the methods for applying Medical
> Maggots to a wound and the methods for insuring that the insects do
> not migrate from the initial site of application to unprotected skin
> around the margin of a wound.
>
> Because, Medical Maggots may be a biohazard after use, product
> labeling should also provide adequate instructions for destroying and
> disposing of the product after use.
>
> The following suggestions are aimed at assisting you in preparing
> labeling that satisfies the requirements of 21 CFR § 807.87(e).
>
> For prescription use, under 21 CFR § 801.109, Medical Maggots are
> 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.
>
> **[Intended Use/Indications for Use]{.underline}**
>
> With regard to indications for use, we recommend that you describe the
> type of surgical cases for which Medical Maggots will be used (e.g.,
> pressure ulcers, venous stasis ulcers, neuropathic foot ulcers and
> non-healing traumatic or post-surgical wounds).

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Charles N. Durfor, Ph.D. Date

FDA/CDRH/ODE/DGRND/PRSB

**TAB 4**

**Medicinal Leeches**

**[Device Definition]{.underline}**

FDA is proposing the following identification for Medicinal Leeches:

> Medicinal Leeches (*Hirudo medicinalis*) are freshwater Annelida worms
> intended for use as an adjunct to the graft tissue healing (when
> problems of venous congestion may delay healing) or to overcome the
> problem of venous congestion by creating prolonged localized bleeding.

FDA currently regulates Medicinal Leeches intended for use as adjuncts
to graft tissue healing (when problems of venous congestion may delay
healing) or to overcome the problem of venous congestion by creating
prolonged localized bleeding as unclassified pre-amendment medical
devices. One product has been cleared for marketing.

FDA's rationale for recommending that this device be a Class II medical
device can summarized as follows:

-   There are many years of experience documenting the clinical use of
    this device category

-   The device specifications and performance characteristics (bench
    testing, animal testing and clinical data) needed to evaluate and
    control the safe and effective use of these devices are known.

-   Control of these products as Class II medical devices meets the FDA
    mandate to apply the "least burdensome" approach to regulating
    medical devices

**[Device Summary and Intended Use/Indications:]{.underline}**

*An extract from "A Sanguine Attachment 2000 Years of Leeches in
Medicine" by Roy T Sawyer Managing Director, Biopharm. Encyclopedia
Britannica INC found at* From - *http://www.biopharm-leeches.com/*

"The pioneering use of leeches in modern plastic and reconstructive
surgery can be attributed to two Slovenian surgeons, M. Derganc and F.
Zdravic from Ljubljana who published a paper in the British Journal of
Plastic Surgery in 1960 describing leech-assisted tissue flap surgery
(in which a flap of skin is freed or rotated from an adjacent body area
to cover a defect or injury). These surgeons credit their own use of
leeches to a Parisian surgeon, one Philippe-Frédéric, who reported in
1836 that he had used leeches to restore circulation following
reconstruction of a nose.

The rationale behind the use of leeches in surgical procedures is fairly
straightforward; nonetheless, it is subject to misunderstanding, even by
clinicians. The key to success is the exploitation of a unique property
of the leech bite, namely, the creation of a puncture wound that bleeds
literally for hours. The leech\'s saliva contains substances that
anaesthetize the wound area, dilate the blood vessels to increase blood
flow, and prevent the blood from clotting.

Microsurgeons today are adept at reattaching severed body parts, such as
fingers. They usually have little trouble attaching the two ends of the
arteries, because arteries are thick-walled and relatively easy to
suture. The veins, however, are thin-walled and especially difficult to
suture, particularly if the tissue is badly damaged. All too often the
surgeon can get blood to flow in the reattached arteries but not veins.
With the venous circulation severely compromised, the blood going to the
reattached finger becomes congested, or stagnant; the reattached portion
turns blue and lifeless and is at serious risk of being lost. It is
precisely in such cases that leeches are summoned."

**[Risk to Health]{.underline}**

FDA currently regulates Medicinal Leeches as an unclassified medical
device. FDA cleared one pre-market notification (510(k)) application for
Medicinal Leeches devices. We searched medical device reports for
device-related adverse events and found no adverse events reported.

The following literature articles are indicative of the published
literature on Medicinal Leeches. These articles also describe some
potential risks of using these devices. They are provided in this
package under **TAB 7**.

-   Conforti, Michael L. D.V.M., M.S.; Connor, Nadine P. Ph.D.; Heisey,
    Dennis M. Ph.D.; Hartig, Gregory K. M.D., ***"***Evaluation of
    Performance Characteristics of the Medicinal Leech (Hirudo
    medicinalis) for the Treatment of Venous Congestion. *" Plastic &
    Reconstructive Surgery*, **109(1)**:228-235, January 2002.

```{=html}
<!-- -->
```
-   [Valauri
    FA](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&term="Valauri+FA"%5BAuthor%5D).,
    "The use of medicinal leeches in microsurgery", *Blood Coagul
    Fibrinolysis*. 1991 Feb; **2(1):**185-7.

```{=html}
<!-- -->
```
-   [Dabb
    RW](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&term="Dabb+RW"%5BAuthor%5D),
    [Malone
    JM](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&term="Malone+JM"%5BAuthor%5D),
    [Leverett
    LC](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&term="Leverett+LC"%5BAuthor%5D).,
    "The use of medicinal leeches in the salvage of flaps with venous
    congestion." *Ann Plast Surg*. 1992 Sep; **29(3)**:250-6.

-   [Mackay
    DR](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&term="Mackay+DR"%5BAuthor%5D),
    [Manders
    EK](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&term="Manders+EK"%5BAuthor%5D),
    [Saggers
    GC](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&term="Saggers+GC"%5BAuthor%5D),
    [Banducci
    DR](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&term="Banducci+DR"%5BAuthor%5D),
    [Prinsloo
    J](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&term="Prinsloo+J"%5BAuthor%5D),
    [Klugman
    K](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&term="Klugman+K"%5BAuthor%5D).
    "Aeromonas species isolated from medicinal leeches", *Ann Plast
    Surg.* 1999 Mar; **42(3):**275-9.

In the table below, the risks to health generally associated with the
use of the Medicinal Leeches are identified. The measures recommended to
mitigate these identified risks are also shown in the table below.

+-----------------------------------+----------------------------------+
| **Identified Risk**               | **Recommended Mitigation         |
|                                   | Measures**                       |
+-----------------------------------+----------------------------------+
| **Adverse tissue reactions**      | Biocompatibility                 |
|                                   |                                  |
|                                   | Device Manufacture               |
|                                   |                                  |
|                                   | Clinical Data                    |
|                                   |                                  |
|                                   | Labeling                         |
+-----------------------------------+----------------------------------+
| **Infection**                     | Sterility and Disinfection       |
|                                   |                                  |
|                                   | Device Manufacture               |
|                                   |                                  |
|                                   | Animal Derived Components        |
|                                   |                                  |
|                                   | Clinical Data                    |
|                                   |                                  |
|                                   | Labeling                         |
+-----------------------------------+----------------------------------+

As stated earlier, this unclassified device will be classified into
Class II which will be subject to special controls.

**[Special Controls Guidance Document:]{.underline}**

For a proposed Medicinal Leeches document, sections 1 through 4 should
be mostly boilerplate language except for references to the device type
and regulation numbers. For your information and review we are providing
some suggestions for the content being considered for inclusion in
Sections 5 through 12 of a draft special controls guidance document for
Medicinal Leeches. Please note that the information presented in this
memorandum is suggested content and, therefore, the exact format and
information contained in any draft special controls guidance document is
subject to change.

**Suggested Content for Sections 5-12**

# [Section 5-Device Description]{.underline}

We recommend that you provide the following device description
information:

-   A description of the genus and species of the proposed product.

-   The methods for packaging and transport of the Medicinal Leeches to
    insure viability.

-   Identification of any other patient contact material such as wound
    dressings or pouches used to retain the Medicinal Leeches at the
    site of application.

-   A description of the storage conditions and time (between shipping
    and device use) that are known to result in safe and effective
    product use.

-   Because Medicinal Leeches are an endangered species, the 510(k)
    application should provide documentation that all appropriate
    importation and exportation requirements have been addressed by the
    manufacturer.

# [Section 6-Risks to Health]{.underline}

This section would include information quite similar to the table above,
which discusses the risks to health associated with the use of Medicinal
Leeches. The information to be placed in that chapter is proposed as
follows:

> In the table below, FDA has identified the risks to health generally
> associated with the use of the Medicinal Leeches addressed in this
> document. The measures recommended to mitigate these identified risks
> are given in this guidance document, as shown in the table below. You
> should also conduct a risk analysis, before submitting your 510(k), to
> identify any other risks specific to your device. 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, you should
> provide sufficient detail to support the approach you have used to
> address that risk.

+------------------------------+---------------------------------------+
| **Identified Risk**          | **Recommended Mitigation Measures**   |
+------------------------------+---------------------------------------+
| **Adverse tissue reactions** | Section 7: Biocompatibility           |
|                              |                                       |
|                              | Section 9: Device Manufacture         |
|                              |                                       |
|                              | Section 11: Clinical Data             |
|                              |                                       |
|                              | Section 12: Labeling                  |
+------------------------------+---------------------------------------+
| **Infection**                | Section 8: Sterility and Disinfection |
|                              |                                       |
|                              | Section 9: Device Manufacture         |
|                              |                                       |
|                              | Section10: Animal Derived Components  |
|                              |                                       |
|                              | Section 11: Clinical Data             |
|                              |                                       |
|                              | Section 12: Labeling                  |
+------------------------------+---------------------------------------+

# [Section 7-Biocompatibility"]{.underline}

This chapter discusses the biocompatibility testing FDA would recommend.
The information proposed for inclusion into this chapter is as follows:

> Depending on the methods of product manufacturing and other
> patient-contacting materials in the shipping medium, FDA recommends
> that you consider conducting biocompatibility testing recommended in
> the FDA-modified **Use of International Standard ISO-10993, Biological
> Evaluation of Medical Devices Part-1: Evaluation and Testing.** We
> recommend that testing be conducted on extracts of the final Medicinal
> Leech product ready for shipping. Because the final product will be in
> contact with breached skin for less than 30 days, we recommend that
> the following tests be evaluated:

-   cytotoxicity

-   sensitization

-   irritation or intracutaneous reactivity

# [Section 8-Sterility and Disinfection]{.underline}

This chapter discusses the information concerning sterilization and
disinfection that FDA would recommend be included in the application.
The information proposed for inclusion into this chapter is as follows:

> As a living organism, Medicinal Leeches cannot be sterilized. However,
> if the shipping container or other device components undergo
> sterilization, the following information should be provided:
>
> 1\. The method of sterilization;
>
> 2\. The validation method for the sterilization cycle;
>
> 3\. The sterility assurance level (SAL) to be achieved; and
>
> 4\. The method for monitoring the sterility of each production lot.
>
> For addition guidance, review of **510(k) Sterility Review Guidance
> K90-1; Final Guidance for Industry and FDA**,
> (<http://www.fda.gov/cdrh/ode/guidance/361.html>) is recommended.
>
> In addition, any procedures used (e.g., antibiotic solutions) to
> reduce the presence of A. hydrophila or other pathogenic bacteria on
> the surface or in the gut of the leeches, should be fully described.
> Such information would not only include information about the
> FDA-approved source of the antibiotic(s) used, but also the residual
> levels of antibiotic(s) remaining in the final product.

# [Section 9-Device Manufacture]{.underline}

This chapter discusses the information concerning device manufacture
that FDA would recommend be incldued in the application. The information
proposed for inclusion into this chapter is as follows:

> The application should contain information about all reagents and
> processing steps used in device manufacture. Information about the
> source and purity of reagents (e.g., CoA and/or MSDS) can be very
> helpful in evaluating the substantial equivalence of proposed and
> legally marketed devices.
>
> Information should also be provided about the methods of manufacturing
> any ancillary wound dressings or pouches used to maintain the devices
> at their initial site of patient application.

# 

# [Section 10-Animal Derived Material]{.underline}

This chapter discusses the information and testing related to
animal-derived material that FDA would recommend be incldued in the
application. The information proposed for inclusion into this chapter is
as follows:

> Because growth and maintenance of Medicinal Leeches may require
> feeding with animal tissue (e.g., blood), information for each animal
> reagent used should be fully described in a 510(k) application or by
> reference to other regulatory submissions (e.g., Master File, PMA,
> 510(k)), when a letter of cross reference is provided. For each animal
> tissue, regulatory applications and facility records should describe
> the following test methods and results:
>
> **Control of Animal Tissue Collection**

-   Animal species

-   Specific tissue(s) used

-   Animal country of origin and residence (more specific geographic
    location when appropriate)

-   Methods for monitoring the health of herd and the health of the
    specific animals from which tissue are collected (including herd
    vaccinations such as live modified viruses that can co-purify in the
    desired tissue)

-   USDA status of the abattoir

-   Methods and conditions for transporting animal tissue

-   Procedures for maintaining records on the above cited issues should
    be presented in regulatory submissions

-   Records of the corresponding test results for each lot of material
    should be maintained at the manufacturing facility or submitted in
    regulatory documents when appropriate

> **Manufacturing Controls for Animal Tissue Components**

-   Test methods and release criteria permitting animal tissues to be
    further processed and/or combined with other animal tissue or device
    components for device manufacture

-   Quaratine procedures for tissues that have not met the release
    criteria

-   Test methods and acceptance criteria for assessing in-process and
    final product bioburden/sterility

-   Methods for facility decontamination/sterilization so that
    cross-contamination is avoided

-   Procedures for maintaining records of the above cited issues should
    be provided in regulatory submissions

-   Records of the corresponding test results for each lot of material
    should be maintained at the manufacturing facility or submitted in
    regulatory documents when appropriate

> **Eliminating Viral Contaminates**
>
> The 510(k) should document all appropriate methods for eliminating
> human infectious agents from the animal tissue used in device
> production. This may include when appropriate, evaluating the ability
> of processing methods and disinfection techniques to inactivate and
> remove viruses.
>
> Such data may be obtained by determining the amount of virus in the
> unprocessed source material and the viral inactivation properties of
> scaled down versions of the specific production and sterilization
> methods (e.g., acid extraction of collagen or dry heat sterilization)
> using appropriate model viruses. The results of these studies should
> demonstrate that the sum of the log clearance of virus from the
> selected processing steps and sterilization processes are at least six
> logs greater than the concentration of virus anticipated in the
> unprocessed source material.
>
> In addition, if bovine material derived from a country in which Bovine
> Spongiform Encephalopathy (BSE) has been observed or a country which
> presents a significant risk of BSE (See 9 CFR § 94.18), the
> application should include a certification that the herd is not
> infected with (BSE). This certification may require information such
> as a herd history, descriptions of the methods use to isolate the
> herd, including the sources of breeding stock, the control of feeds,
> the disposition of animals with central nervous system signs, and
> testing for the BSE agent. Certification that the material was not
> processed using equipment contaminated by animal materials from other
> herds may also be requested.

# [Section 11-Clinical Data]{.underline}

This section discusses the related to clinical experience that FDA would
recommend be incldued in the application. The information proposed for
inclusion into this chapter is as follows:

> The application should provide a summary of any clinical experience
> obtained with the device. Reference to the appropriate 510(k), PMA or
> IDE number (or cited as overseas experience) may greatly simplify the
> review process when appropriate letters of cross-reference are
> included in the application.

# [Section 12-Labeling]{.underline}

This section should discuss the information and testing related to
product labeling that FDA would recommend be incldued in the
application. The information proposed for inclusion into this chapter is
as follows:

The pre-market 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 Part 801.[^1]

The following suggestions are aimed at assisting you in preparing
labeling that satisfies the requirements of 21 CFR § 807.87(e). For
prescription use, under 21 CFR § 801.109, Medicinal Leeches are 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.

> **Directions for 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 recommend submitting 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]{.underline}**:
>
> The instructions should describe the methods for applying Medicinal
> Leeches to the patient and the methods for insuring that the insects
> do not migrate from the initial site of application.
>
> Because, Medicinal Leeches may be a biohazard after use, product
> labeling should also provide adequate instructions for destroying and
> disposing of the product after use.
>
> **[Intended Use/Indications for Use]{.underline}**
>
> With regard to indications for use, we recommend that you describe the
> type of surgical cases for which Medicinal Leeches will be used (e.g.,
> graft tissue healing).

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Charles N. Durfor, Ph.D. Date

FDA/CDRH/ODE/DGRND/PRSB

> **TAB 5**
>
> **Tissue Expanders**

To date FDA has regulated tissue expanders as unclassified pre-amendment
medical devices.

**Proposed Classification of a Tissue Expander Device**

> "A tissue expander is an inflatable silicone elastomer shell filled
> with Normal Physiological Saline (injection grade) intended for
> temporary implantation to develop surgical flaps and additional tissue
> coverage in a variety of applications, such as breast reconstruction
> following mastectomy, treatment of underdeveloped breasts, scar
> revision, and treatment of soft tissue deformities or injuries. The
> tissue expander is intended for temporary subcutaneous or submuscular
> implantation and is not intended for use beyond 6 months."

Tissue expanders are available in many different shapes (e.g., round,
rectangular). Tissue expansion is a procedure that enables the body to
\"grow\" extra skin for use in reconstructing almost any part of the
body. The tissue expander is inserted under the skin near the area to be
expanded and then gradually filled with Normal Physiological Saline
(injection grade, with a concentration of 0.15M and a pH of 7.2-7.4)
over time, causing the skin to stretch and grow.

The tissue expander is intended for temporary implantation to develop
surgical flaps and additional tissue coverage in a variety of
applications, such as breast reconstruction following mastectomy,
treatment of underdeveloped breasts, scar revision, and treatment of
soft tissue deformities or injuries. The tissue expander is intended for
temporary subcutaneous or submuscular implantation and is not intended
for use beyond 6 months.

To date the Tissue Expanders FDA has cleared have been composed of
silicone. FDA has classified several silicone devices as class III,
class II, class I and unclassified devices. For example, breast
implants, which have a silicone elastomer shell with a saline or
silicone gel filler, is regulated through the pre-market approval (PMA)
process as class III medical device. FDA wants to stress that tissue
expander devices are considered a different device type than breast
implants, despite some similarities in design. Breast implants are
permanent devices held to a much higher standard of review than tissue
expanders, which are temporary devices with a different intended use
(i.e., stretch the skin). On the other hand, silicone chin, facial, etc.
implants are regulated as class II medical devices. Several other
medical devices made of silicone are class I devices and are exempt from
510(k) requirements (e.g., drainage tubes). Tissue expanders are
currently regulated as an unclassified medical device and are considered
an implanted device, as they are within the body for \>30 days (but for
a maximum of 6 months).

**[Proposed Identification for the Tissue Expander Device]{.underline}**

FDA is proposing the following identification for the tissue expander
device:

> "A tissue expander is an inflatable silicone elastomer shell filled
> with Normal Physiological Saline (injection grade) intended for
> temporary implantation to develop surgical flaps and additional tissue
> coverage in a variety of applications, such as breast reconstruction
> following mastectomy, treatment of underdeveloped breasts, scar
> revision, and treatment of soft tissue deformities or injuries. The
> tissue expander is intended for temporary subcutaneous or submuscular
> implantation and is not intended for use beyond 6 months."

**[Tissue Expanders Cleared through the 510(k) Process]{.underline}**

FDA has received 45 510(k)s in the time period of 1978 to 2004. In
general, round tissue expander devices have been cleared for breast
reconstruction after mastectomy, correction of an underdeveloped breast,
scar revision, and tissue defect procedures. Rectangular tissue
expanders have been cleared for preparation for closure of defects after
resection of large tumors (e.g., nevi, basiloma, etc.), scar correction,
if primary direct closure is not possible, and preloading of local flaps
(e.g., at forehead). Table 1 below contains a list of some of the most
recently cleared 510(k)s for tissue expanders.

**Table 1: Tissue Expanders recently cleared through (510(k) process.**

+--------+-----------+-------+---------+-----------------------------+
| **Pro  | **        | **5   | *       | **Indication**              |
| duct** | Sponsor** | 10(k) | *Common |                             |
|        |           | Num   | Name**  |                             |
|        |           | ber** |         |                             |
+========+===========+=======+=========+=============================+
| Mentor | Mentor    | K0    | Tissue  | The Contour Profile Tissue  |
| C      | Corp.     | 11500 | E       | Expander can be utilized    |
| ontour |           |       | xpander | for breast reconstruction   |
| P      |           |       |         | after mastectomy,           |
| rofile |           |       |         | correction of an            |
| Tissue |           |       |         | underdeveloped breast, scar |
| Ex     |           |       |         | revision, and tissue defect |
| pander |           |       |         | procedures. The device is   |
|        |           |       |         | intended for temporary      |
|        |           |       |         | subcutaneous or submuscular |
|        |           |       |         | implantation and is not     |
|        |           |       |         | intended for use beyond six |
|        |           |       |         | months.                     |
+--------+-----------+-------+---------+-----------------------------+
| B      | Wells     | K9    | S       | Breast reconstruction, limb |
| ircoll | Johnson   | 84448 | urgical | reconstruction, correction  |
| B      | Co.       |       | Balloon | of congenital deformities,  |
| alloon |           |       | Diss    | cosmetic defects, scar      |
| Dis    |           |       | ector/E | revision.                   |
| sector |           |       | xpander |                             |
+--------+-----------+-------+---------+-----------------------------+
| Seare  | Seare     | K9    | Ex      | Seare Biomedical Silicone   |
| Biom   | B         | 83792 | pander, | Tissue Expanders are        |
| edical | iomedical |       | Skin    | intended for temporary      |
| Si     | Corp.     |       | I       | subcutaneous implantation   |
| licone |           |       | nflator | to develop surgical flaps   |
| Tissue |           |       |         | and additional tissue       |
| Ex     |           |       |         | coverage required in a wide |
| pander |           |       |         | variety of applications,    |
|        |           |       |         | particularly to aid in      |
|        |           |       |         | reconstruction following    |
|        |           |       |         | mastectomy, to aid in the   |
|        |           |       |         | treatment of underdeveloped |
|        |           |       |         | breasts, and to aid in the  |
|        |           |       |         | treatment of soft tissue    |
|        |           |       |         | deformities.                |
+--------+-----------+-------+---------+-----------------------------+
| Hutc   | Hutchison | K9    | Tissue  | The Hutchinson Inflatable   |
| hinson | Intl. Inc | 83385 | E       | Silicone Tissue Expanders   |
| Infl   |           |       | xpander | are designed for temporary  |
| atable |           |       |         | use in:                     |
| Si     |           |       |         |                             |
| licone |           |       |         | -   Scar/defect revision    |
| Tissue |           |       |         |                             |
| Ex     |           |       |         | -   Reconstruction of the   |
| pander |           |       |         |     breast following        |
|        |           |       |         |     subcutaneous mastectomy |
|        |           |       |         |     and other suitable      |
|        |           |       |         |     procedure or trauma     |
|        |           |       |         |                             |
|        |           |       |         | -   Breast underdevelopment |
|        |           |       |         |     and other combined      |
|        |           |       |         |     breast and chest wall   |
|        |           |       |         |     abnormalities           |
+--------+-----------+-------+---------+-----------------------------+
| Ma     | S         | K9    | S       | Silicone Tissue Expanders   |
| gnetic | peciality | 82067 | ilicone | are intended for temporary  |
| Port   | Surgical  |       | Tissue  | subcutaneous implantation   |
| Si     | Products  |       | E       | to develop surgical flaps   |
| licone |           |       | xpander | and additional tissue       |
| Tissue |           |       |         | coverage required in a wide |
| Ex     |           |       |         | variety of applications,    |
| pander |           |       |         | particularly to aid in      |
|        |           |       |         | reconstruction following    |
|        |           |       |         | mastectomy, to aid in the   |
|        |           |       |         | treatment of underdeveloped |
|        |           |       |         | breasts, and to aid in the  |
|        |           |       |         | treatment of soft tissue    |
|        |           |       |         | deformities.                |
+--------+-----------+-------+---------+-----------------------------+
| S      | Silimed   | K9    | Tissue  | Silimed tissue expanders    |
| ilimed | LLC       | 81852 | E       | are intended for temporary  |
| Tissue |           |       | xpander | subcutaneous implantation   |
| Ex     |           |       |         | to develop surgical flaps   |
| pander |           |       |         | and additional tissue       |
|        |           |       |         | coverage required in a wide |
|        |           |       |         | variety of applications,    |
|        |           |       |         | particularly to aid in      |
|        |           |       |         | reconstruction following    |
|        |           |       |         | mastectomy, to aid in the   |
|        |           |       |         | treatment of underdeveloped |
|        |           |       |         | breasts, and to aid in the  |
|        |           |       |         | treatment of soft tissue    |
|        |           |       |         | deformities.                |
+--------+-----------+-------+---------+-----------------------------+

**[Medical Device Reporting (MDR) System Summary]{.underline}**

In order to assess the potential risks associated with the use of tissue
expanders, we reviewed the adverse event reports submitted to the FDA
via the MDR System. This system involves voluntary reporting from 1992
until 1996, after which it became mandatory for manufacturers to report
any device failures they were aware of. The MDRs for tissue expanders
received by FDA are summarized in Tables 2 and 3 below, stratified by
device and patient problems, respectively, for the time period 1976
through June 2005. As a note, the majority of the device and patient
problems were reported in the early years 1993 to 1994.

**Table 2: Adverse Events Reported; Top Device Problems**

  ---------- -------------------------------------------- -----------------
  **Rank**   **Adverse Events**                           **Total**

  1          Explanted                                    179

  2          Deflation, cause unknown                     72

  3          Leaks(s)                                     64

  4          Replace                                      49

  5          Implant Removal                              43

  6          Invalid Data                                 33

  7          Rupture, cause unknown                       25

  8          Device Failure                               16

  9          Tears, rips, holes in device, device         15
             material                                     

  10         Fluid leak(s)                                14
  ---------- -------------------------------------------- -----------------

Of a total of 694 device problems reported, the top device problems were
explantation (25.79%), deflation (cause unknown) (10.37%), and leaks
(9.22%).

**Table 3: Adverse Events Reported; Top Patient Problems**

  ---------- -------------------------------------------- -----------------
  **Rank**   **Adverse Events**                           **Total**

  1          Surgical Procedure                           153

  2          Surgical procedure, repeated                 67

  3          Infection                                    49

  4          Pain                                         39

  5          Invalid Data                                 48

  6          Capsular contracture                         37

  7          Implant failure                              33

  8          Unknown (patient's condition not known)      31

  9          Hospitalization required                     30

  10         Fatigue                                      18
  ---------- -------------------------------------------- -----------------

Of a total of 857 patient problems reported, the top patient problems
were surgical procedure (17.85%), surgical procedure - repeated (7.82%),
and infection (5.72%).

**[Literature Summary]{.underline}**

In order to further assess the potential risks associated with the use
of tissue expanders, we reviewed the published literature. The following
literature articles are considered representative of what is available
in the published literature for tissue expanders. These articles discuss
tissue expanders and also describe some potential risks of using these
devices. Copies of these articles are provided in **TAB 7.**

-   A history of tissue expansion. Concepts, controversies, and
    complications.

Bennett RG, Hirt M, J Dermatol Surg Oncol. 1993 Dec; 19(12): 1066-73

-   Evolution of the concept of tissue expansion.

Austad ED, Facial Plast Surg. 1988 Jul; 5(4): 277-9.

-   The expansion of an area of skin by progressive distention of a
    subcutaneous balloon; use of the method for securing skin for
    subtotal reconstruction of the ear.

> Neumann CG, Plast Reconstr Surg. 1957 Feb; 19(2): 124-30

-   Tissue Expansion

> Author: Don R Revis, Jr; Co-author: Michael B Seagel,
> <http://www.emedicine.com/ent/topic708.htm>

**[Risks to Health]{.underline}**

The risks to health for tissue expanders were assessed by the review of
MDRs, the published literature, and the 510(k)s of cleared tissue
expanders. Accordingly, FDA believes that the risks to health for tissue
expanders can be grouped into the following risk categories:

-   device failure (rupture, injection site/valve failure)

-   skin trauma (necrosis, thinning, sloughing)

-   infection

-   adverse tissue reaction.

Additional information regarding the risks to health and controls to
mitigate them are included in Table 4 below, as well as control that we
are proposing to address the risk.

**[Special Controls Guidance Document]{.underline}**

For a proposed Tissue Expander document, sections 1-3 should consist of
primarily boilerplate language except for references to the device type
and regulation numbers. Section 4 would be the Scope section, which
would identify the limitations in terms of device description and
intended use/indications. It will include the identification information
similar to that in part 3 of this review memo, as well as the CFR
identification number and procode information.

For your information and review we are providing some suggestions for
the content being considered for inclusion in Sections 5 through 10 of a
proposed draft special controls guidance document for Tissue Expanders.
Please not that the information presented in this memorandum is
suggested content and therefore, the exact format and information
contained in any draft special control document is subject to change.

**Suggested Content for Sections 5 through 10**

**[Section 5 -- Device Description]{.underline}**

Although this is not a control that will be used to mitigate the
identified risks to health, FDA believes that this section will provide
much of the information that FDA needs to complete the review of a
tissue expander device.

The proposed information for this section is as follows:

> This section provides the type of device description information that
> we recommend that you include in your submission. However, depending
> on the particular design of your tissue expander, additional
> information may be recommended.

We recommend that you provide the following device description
information:

-   a written description of each component that comprises the tissue
    expander (e.g., shell, patch, injection port/valve)

-   magnified sketches of each component

-   a table that provides the specific material and supplier for each
    component of the tissue expander

-   a description of the mechanism for filling the implant (e.g.,
    magnetic port, injection dome), including magnified sketches of the
    implants, depicting the placement/use of the connector systems, fill
    tubes, and injection domes

-   a description of the sealing mechanism of an injection site

-   the following summary table of all tissue expanders under review
    (example of information included):

+-----+-------+-----------+-------+------+------+--------+----------+
| **S | **    | ##        | **Vol | *    | **   | **     | *        |
| tyl | Shell | ## Shape  | ume** | *Wid | Heig | Projec | *Range** |
| e** | Surf  | / Profile |       | th** | ht** | tion** |          |
|     | ace** |           | **(   |      |      |        | **Shell  |
|     |       |           | cc)** | **(c | **(c | **     | Thi      |
|     |       |           |       | m)** | m)** | (cm)** | ckness** |
+-----+-------+-----------+-------+------+------+--------+----------+
| X   | S     | Round,    | 12    | 9-16 | 8.   | 3      | 0.015    |
| XXX | mooth | High      | 5-650 |      | 4-15 | .1-5.7 | "-0.043" |
+-----+-------+-----------+-------+------+------+--------+----------+

**[Section 6 -- Risks to Health]{.underline}**

This section would include the risks to health and the controls that we
believe would mitigate the risks. The proposed information for this
section is as follows:

> In the table below, FDA has identified the risks to health generally
> associated with the use of the tissue expander 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 conduct a risk analysis to identify any
> other risks specific to your device and submit the results of this
> analysis. 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, you should provide sufficient
> detail to support the approach you have used to address that risk.

+------------------------------------+---------------------------------+
| **Identified Risk**                | **Recommended Mitigation        |
|                                    | Measures**                      |
+------------------------------------+---------------------------------+
| Skin trauma (e.g., necrosis,       | Section 10: Labeling            |
| thinning, sloughing)               |                                 |
+------------------------------------+---------------------------------+
| Device failure (e.g., rupture,     | Section 7: Preclinical testing  |
| injection site/valve failure)      |                                 |
|                                    | Section 10: Labeling            |
+------------------------------------+---------------------------------+
| Infection                          | Section 8: Sterility            |
+------------------------------------+---------------------------------+
| Adverse tissue reaction            | Section 9: Biocompatibility     |
+------------------------------------+---------------------------------+

**[Section 7 -- Preclinical Testing]{.underline}**

This section would include preclinical testing for a tissue expander.
The proposed information for this section is as follows:

> This section provides the type of preclinical testing that we
> recommend that you include in your submission. However, depending on
> the particular design of your tissue expander, additional information
> may be recommended.
>
> **[Material Property Testing of the Shell]{.underline}**
>
> Please provide complete reports of material property testing (e.g.,
> tensile strength, % elongation, tensile set, joint testing) of your
> subject device compared to a predicate device. All testing should be
> performed on components from the final, sterilized product. As part of
> the test report, please provide a description of the test set-up and
> methods, and state which tissue expanders were tested (e.g., model,
> size).
>
> **[Injection Site Testing]{.underline}**
>
> We recommend that you provide appropriate preclinical testing to show
> that your tissue expander can be accessed accurately through the skin.
> For example, if your device has a magnetic port to locate the
> injection site, please provide data that show you can accurately
> access that site through the skin.
>
> In addition, please provide appropriate preclinical testing to show
> how many punctures the injection site of your tissue expander can
> handle before compromising the material integrity of the site.
>
> **[Valve Competency Testing]{.underline}**
>
> If your tissue expander includes a valve for postoperative filling, we
> recommend that you provide valve competency testing to demonstrate
> that valve integrity is maintained at *in vivo* loads. Although ASTM
> 2051 is intended for saline-filled breast implants, FDA believes that
> this test methodology would be applicable for a tissue expander with a
> valve. ASTM F2051 states that there shall be no leakage observable
> after a normally closed valve is subjected to a retrograde pressure
> equivalent to 30cm H~2~O for 5 minutes and then to a retrograde
> pressure equivalent to 3cm H~2~O for 5 minutes. FDA does not believe
> that the load levels described in the ASTM F2051 methodology are
> clinically relevant; however, this methodology may provide useful
> information in terms of the valve handling shifts in pressure.
> Therefore, you should provide a complete report of valve competency
> testing as per ASTM F2051. You should provide the pass/fail results
> for leakage.
>
> In addition to the testing above, you should perform destructive
> testing to address *in vivo* loading conditions. Gradually load the
> samples until valve failure occurs to define a maximum pressure for
> the device. Please provide the burst pressures, the failure modes
> (including whether the failed test valves reseal upon removal of the
> excess failure-inducing pressures), and the clinical rationale for the
> resulting burst pressures.

**[Self-Sealing Patch Testing]{.underline}**

> If your tissue expander has a self-sealing patch, we recommend that
> you provide a complete report of preclinical testing that shows that a
> punctured patch can self-seal and maintain that self-seal for the
> entire duration of the use of the tissue expander.

**[Section 8 -- Sterility]{.underline}**

This wording in this section is essentially consistent across guidance
documents for medical devices. The proposed information for this section
is as follows:

> FDA recommends that you provide sterilization information in
> accordance with the **Updated 510(k) Sterility Review Guidance K90-1;
> Final Guidance for Industry and FDA**,
> [http://www.fda.gov/cdrh/ode/guidance/361.html]{.underline}. The
> device should be sterile with a sterility assurance level (SAL) of 1 x
> 10^-6^.

**[Section 9 -- Biocompatibility]{.underline}**

This wording in this section is also essentially consistent across
guidance documents for medical devices. The proposed information for
this section is as follows:

> FDA recommends that you conduct biocompatibility testing 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>, for blood-contacting,
> long-term implanted devices.  We recommend that you select
> biocompatibility tests (Parts 5 and 10 of ISO-10993) appropriate for
> the duration and level of contact with your device.  If *identical*
> materials are used in a predicate device with the same type and
> duration of patient contact, you may identify the predicate device in
> lieu of providing biocompatibility testing.

**[Section 10 -- Labeling]{.underline}**

This last section of the guidance document provides recommendations for
the labeling specific to the tissue expander device. The proposed
information for this section is as follows:

> 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 Part 801.[^2]
>
> **Directions for 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 recommend submitting 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.
>
> In addition, we recommend that the labeling include:

-   device name, style, etc.

-   name and address of manufacturer, packer, or distributor

-   "Sterile," "Do not re-sterilize," and "Single use only" notations
    (or similar wording)

-   expiration date

-   brief device description with material information

-   indications for use

-   any relevant contraindications (including patient groups in which
    the implant is contraindicated, surgical procedures which are
    contraindicated due to interference with implant integrity and/or
    performance), warnings (e.g., if device has a magnetic port, it
    should therefore not be used in patients who have implanted devices
    that could be affected by a magnetic field), and precautions

-   list of potential complications

-   procedures such as descriptions how to prepare the patient (e.g.,
    prophylactic antibiotics), operating room (e.g., what supplies
    should be on hand), and troubleshooting procedures

-   instructions for implantation, including surgical approach and
    device specific information (depends on type of tissue expander)

-   instructions for proper filling of the expander, intraoperatively
    and postoperatively, including the specific fill volume instructions

-   intraoperative test procedures to ensure implant integrity and
    proper placement (if necessary)

-   instructions for follow-up, including whether patient antibiotic
    prophylaxis is recommended during the post-implant period and during
    any subsequent surgical procedures, postoperative patient care, etc.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Nada O. Hanafi, MSc Date

Biomedical Engineer/Expert Reviewer

Plastic and Reconstructive Surgery Devices Branch

Division of General, Restorative, and Neurological Device

**TAB 6**

**Wound Dressings with Drugs**

Until 1999 all the wound dressings (Non-absorbable Gauze, Hydrogels,
Occlusive Wound Dressings, and Hydrophilic Wound Dressings) with and
without drugs were regulated as unclassified devices. The wound
dressings that do not contain drugs were classified as Class I, exempt
devices. The wound dressings that contain drugs are still regulated as
unclassified devices.

Your panel package includes information on the classification of medical
devices. Please note that some slides of the presentation in TAB 1 on
Device Classification/ Reclassification Procedures have an asterisk
(\*). The asterisked slides pertain to the classification of
unclassified pre-amendment devices and are relevant to the
classification of the wound dressing devices containing drug components.
TAB 8 lists our panel discussion topics for the classification of these
devices. TAB 7 contains a bibliography of some articles on the use of
wound dressings with drugs. The product labels for some of the
pre-amendment wound dressing devices with drugs are provided at the end
of this memo.

**Proposed identification of the devices:**

FDA is proposing the following identification for the wound dressings
containing drugs:

*Wound Dressing Containing a Drug:*

A wound dressing containing a drug is a sterile or non-sterile device
product in which the primary mode of action is provided by the device
component. It is intended to cover a wound, to absorb exudate, to
provide or support a moist wound environment, and to control bleeding or
fluid loss. It consists of nonresorbable materials and contains added
drugs such as antimicrobials.

Wound dressings that include drug are considered by the agency to be
combination products. FDA jurisdiction over combination products is
determined by the product's primary mode of action.

FDA currently regulates several wound dressing devices as Class III,
Class I (exempt) and unclassified devices. For example, interactive
wound dressings like Orcel, Dermagraft, and Apligraf which contain live
human cells are regulated as Class III medical devices. Wound dressings
that do not contain drugs such as, e.g., Biobrane, Bard Occlusive Wound
Dressing are regulated as Class I (exempt) devices. The wound dressings
that contain drug components such as, e.g., Silverlon Contact Wound
Dressing, Hydrofera Bacteriostatic Wound Dressing are currently
regulated as unclassified devices.

FDA cleared approximately fifty pre-market notification (510(k))
applications for wound dressing devices containing drug components in
the last 5 years (see Table 1 for examples). We searched medical device
reports for the device adverse events. Some of the adverse events are
reported for these unclassified wound dressings are provided in Table 2.

Table 1 lists some of the recently cleared wound dressings that contain
drugs. These dressing devices were found substantially equivalent to
pre-amendment dressing devices that were in commercial distribution
prior to 1976. These pre-amendment devices include Mercurochrome
marketed since 1929 and Borated Band-Aid bandage marketed since 1924 by
J & J, the labels of which are included at the end of this memo.

**Table 1: Wound Dressings with Drugs**

+----------------+----------------+---------+-------------------------+
| **Product,     | **Cha          | *       | **Indication**          |
| Sponsor,       | racteristics** | *Drug** |                         |
| 510(k) \#**    |                |         |                         |
+----------------+----------------+---------+-------------------------+
| Contreet Foam  | Sodium         | Silver  | For deep wounds with    |
| Cavity         | hydrogen       |         | moderate to high        |
| Dressing with  | silver         |         | amounts of exudate such |
| Silver,        | zirconium      |         | as stage II, III, & IV  |
| Coloplast      | phosphate on   |         | pressure ulcers, leg    |
| Corp., K033869 | polyurethane   |         | ulcers and burns, but   |
|                | film           |         | not third degree burns  |
+----------------+----------------+---------+-------------------------+
| Antimicrobial  | Calcium        | Silver  | An effective barrier to |
| Alginate       | alginate,      |         | bacterial penetration.  |
| Dressing,      | carboxymethyl  |         | The barrier functions   |
| Advanced       | cellulosenylon |         | of the dressing may     |
| Medical        | and elemental  |         | help reduce infection   |
| Solutions,     | silver         |         | in heavily exudating    |
| K024298        |                |         | partial and full        |
|                |                |         | thickness wopunds       |
|                |                |         | including: pressure     |
|                |                |         | ulcers, venous ulcers,  |
|                |                |         | donor sites, traumatic  |
|                |                |         | and surgical wounds     |
+----------------+----------------+---------+-------------------------+
| Hydrofera      | Poly vinyl     | Me      | Local management of     |
| Bacteriostatic | alcohol (PVA)  | thylene | pressure ulcers, donor  |
| Wound          | with two       | Blue    | sites, venous stasis    |
| Dressing,      | organic        | and     | ulcers, arterial        |
| Hydrofera LLC, | pigments,      | Crystal | ulcers, diabetic        |
| K023138        | Methylene Blue | Violet  | ulcers, abrasions,      |
|                | and Crystal    |         | lacerations, and        |
|                | Violet         |         | superficial burns,      |
|                |                |         | post-surgical           |
|                |                |         | incisions, and other    |
|                |                |         | external wounds         |
|                |                |         | inflicted by trauma     |
+----------------+----------------+---------+-------------------------+
| Suile Wound    | Gauze          | Bismuth | For helping healing     |
| Dressing,      | impregnated    | sub     | burns, partial          |
| Hedonist       | with Bismuth   | gallate | thickness wounds, donor |
| Biochemical    | subgallate,    |         | sites, abrasions,       |
| Technologies   | Borneol        |         | surgical incision       |
| Co. Ltd.,      |                |         | sites, colostomies and  |
| K022967        |                |         | urological procedures.  |
+----------------+----------------+---------+-------------------------+
| Inman Xeroform | Gauze          | Bismuth | To be used as a general |
| Petrolatum     | impregnated    | tri     | external wound dressing |
| Dressing,      | with           | bromop- |                         |
| Inman Medical  | petrolatum     | heneate |                         |
| Corp, K921289  | containing     | (e      |                         |
|                | Bismuth-       | xternal |                         |
|                | tr             | anti    |                         |
|                | ibromopheneate | septic) |                         |
+----------------+----------------+---------+-------------------------+
| Actisorb       | Activated      | Silver  | An effective barrier to |
| Silver 220     | charcoal cloth |         | bacterial penetration   |
| Antimicrobial  | impregnated    |         | and for absorbing       |
| Binding        | with silver    |         | offending odor          |
| Dressing, J&J  |                |         | resulting from wounds   |
| Wound          |                |         | -- pressure ulcers,     |
| Management,    |                |         | venous ulcers, diabetic |
| K022483        |                |         | ulcers, first and       |
|                |                |         | second degree burns,    |
|                |                |         | donor sites and         |
|                |                |         | surgical wounds         |
+----------------+----------------+---------+-------------------------+
| Calcium        | Silver         | Silver  | Medium to heavily       |
| A              | alginate foam  |         | exudating wounds        |
| lginate-Silver | with or        |         | including ulcers of the |
| Alginate       | without a      |         | leg, pressure sores,    |
| Topical Wound  | backing.       |         | chronic wounds, first   |
| Dressing,      |                |         | and second degree       |
| ADRI, K011618  |                |         | burns, donor sites.     |
+----------------+----------------+---------+-------------------------+
| Silverlon      | Silver-coated  | Silver  | Local management of     |
| Wound Packing  | nylon wound    |         | lacerations.            |
| Strips,        | packing strip  |         |                         |
|                |                |         |                         |
| Argentum Intl. |                |         |                         |
| LLC, K984210   |                |         |                         |
+----------------+----------------+---------+-------------------------+
| Biopatch       | Polyurethane   | C       | To absorb exudate and   |
| Antimicrobial  | film           | hloro-h | to cover a wound caused |
| Dressing,      | impregnated    | exidine | by the use of vascular  |
| Ethicon,       | with           |         | and non-vascular        |
| K003229        | chlorohexidine |         | percutaneous medical    |
|                | gluconate      |         | devices such as: IV     |
|                |                |         | catheters, central      |
|                |                |         | venous lines, arterial  |
|                |                |         | cathers, peripherally   |
|                |                |         | inserted coronary       |
|                |                |         | catheters, mid-line     |
|                |                |         | catheters, drains,      |
|                |                |         | chest tubes,            |
|                |                |         | exterbnally placed      |
|                |                |         | orthopedic pins, and    |
|                |                |         | epidural catheters. It  |
|                |                |         | is also intended to     |
|                |                |         | reduce local            |
|                |                |         | infections, catheter    |
|                |                |         | related blood stream    |
|                |                |         | infections (CRBSI), and |
|                |                |         | skin colonization of    |
|                |                |         | microorganisms commonly |
|                |                |         | related to CRBSI, in    |
|                |                |         | patients with central   |
|                |                |         | venous or arterial      |
|                |                |         | catheters.              |
+----------------+----------------+---------+-------------------------+

MDR reports for adverse events reported under the product codes FRO were
reviewed and the following adverse events were noted (see Table 2)

**Table 2: Adverse Events Reported**

  -------------------------------------------- --------------------------
  **Adverse Event**                            **Total Events**

  Blistering                                   9

  Injury                                       8

  Severe Burning Pain                          1

  Irritation/Swelling                          2

  Allergic Reaction                            3

  Skin Necrosis                                2

  Inflammation                                 8

  Infection                                    3
  -------------------------------------------- --------------------------

Exemplary of the type of adverse events observed with these devices, as
described in MDR reports are in the following table (Table 3)

**Table 3 MDR Reports of a few wound dressing with drugs**

+------------+--------------------+---------------------+-------------+
| **Device   | **Device           | **Adverse Event**   | **Dev       |
| Name and   | Components**       |                     | ice-related |
| 510(k)     |                    |                     | or not**    |
| \#**       |                    |                     |             |
+------------+--------------------+---------------------+-------------+
| K973507    | Gauze impregnated  | 1.Allergic          | Patient     |
| Kendall    | with petrolatum    | reaction/swelling   | reacted to  |
| Xeroform   | and 3% Bismuth     |                     | the         |
| Petrolatum | bromopheneate      | 2\. Allergic        | dressing.   |
| Dressing   |                    | contact dermatitis  | May be      |
|            |                    |                     | dev         |
|            |                    |                     | ice-related |
+------------+--------------------+---------------------+-------------+
| K991463    | Silver Dressing    | Pain                | Unclear     |
| Silverlon  |                    |                     |             |
+------------+--------------------+---------------------+-------------+
| K003229    | Polyurethan foam   | 1.  Skin "burned"   | Appears to  |
| Biopatch   | with chlorohexidin |     with full       | be          |
| Ant        | (200-300ug/mg)     |     thickness wound | dev         |
| imicrobial |                    |                     | ice-related |
| Dressing   |                    | 2.  Skin injury     |             |
|            |                    |                     |             |
|            |                    | 3.  Blisters        |             |
|            |                    |                     |             |
|            |                    | 4.  Redness         |             |
|            |                    |                     |             |
|            |                    | 5.  Skin breakdown  |             |
+------------+--------------------+---------------------+-------------+
| K013814    | Carb               | 1.  Patient death   | Unclear     |
| Aquacel-Ag | oxymethylcellulose |                     |             |
|            | with ionic silver  | 2.  Patient         |             |
|            |                    |     developed skin  |             |
|            |                    |     necrosis,       |             |
|            |                    |     patient         |             |
|            |                    |     improved after  |             |
|            |                    |     discontinuation |             |
|            |                    |     of the dressing |             |
+------------+--------------------+---------------------+-------------+
| K022416    | Polyurethane foam  | Blisters observed   | May be      |
| Contreet   | containing silver  | at the site of      | dev         |
| Foam       |                    | application         | ice-related |
| Dressing   |                    |                     |             |
+------------+--------------------+---------------------+-------------+

**Rationale for Proposed Class II Regulatory Status for Wound Dressings
with Drugs:\
**

The Agency's rationale for suggesting that this device be classified
into Class II is summarized as follows:

-   We have years of experience regulating these devices (since 1976)

-   We understand the device specifications and performance
    characteristics (bench testing, animal testing and clinical data)
    needed to evaluate and control their safe and effective use.

-   Classification to Class II meets the FDA mandate to apply the "least
    burdensome" approach to regulating medical devices.

The Agency's rationale for identifying a Class II designation as
appropriate is based on the long history of safe and effective use of
these devices over the past 100 years and the scarcity of adverse event
reports in the medical literature and the FDA's Medical Device Reporting
System. The Agency proposes that all of the potential risks to health
can be ameliorated via a special controls guidance document that
includes recommendations and advice on device materials, device
performance, animal testing, clinical testing, device sterilization,
biocompatibility and device labeling.

The recent MDUFMA amendment to the FD&C Act directed the Agency to
regulate medical devices in the "least burdensome" manner possible based
on the available safety and effectiveness information. Please keep this
in mind as you consider classification of these devices. A copy of the
least burdensome guidance document is included in TAB 11 of the panel
pack.

FDA proposes that the wound dressings containing drugs can be regulated
with special controls. Following are the relevant draft sections of a
proposed Wound Dressings with Drugs Guidance Document for your
consideration as you discuss the appropriate classification for this
device.

**Special Controls Guidance Document:**

When the Office of Device Evaluation (ODE) classifies a medical device
into regulatory Class II, such classifications are accompanied by what
the Agency refers to as "Special Controls". In the vast majority of
cases, the special control has been in the form of a guidance document.
A recently published Class II special controls guidance document is
included for your reference TAB 10 of the panel pack. The Class II
special controls guidance document for Wound Dressings with Drugs would
be very similar to the sample guidance document provided with the
exception that specific device information would be different.

While the agency has not provided you with a copy of a draft proposed
special controls guidance document for Wound Dressings with Drugs, this
panel package includes the sections for such a guidance document for
your review. At present, a special controls guidance document is
comprised of 11 chapters. For a proposed absorbable surgical hemostatic
agent devices document, chapters 1 through 4 and 9 through 11 would be
mostly boilerplate language except for references to the device type and
regulation numbers. For your information and review we are providing the
information that is proposed for Chapters 5 through 8 of a special
controls guidance document for wound dressings with drugs. Please note
that the information presented in this memorandum is in draft form and,
therefore, the exact format and information contained in the final
guidance document is subject to change.

Wound dressings containing a drug component are combination products for
which the primary purpose of the dressing is a device function. For
combination products for which the primary purpose is not clearly a
device, the sponsor should contact the Office of Combination products at
<http://www.fda.gov/oc/combination/>.

A drug is defined in Section 201(g)(1) of the Federal Food, Drug and
Cosmetic Act and may be searched in the Orange Book at
<http://www.fda.gov/ob>.

***Chapter 5, "Risks to Health":***

> This chapter discusses risks to health associated with the use of
> wound dressings containing drugs. The information to be placed in that
> chapter is proposed as follows:
>
> In the table (Table 4) below, FDA has identified the risks to health
> generally associated with the use of wound dressings containing drugs.
> The measures recommended to mitigate these identified risks are given
> in this guidance document, as shown in the table below. A risk
> analysis should be conducted prior to submitting your 510(k), to
> identify any other risks specific to the device. The 510(k) should
> describe the risk analysis method. If an alternative approach was
> elected to address a particular risk identified in this document, or
> there are additional risks identified other than those in this
> document, sufficient details to support the approach should be
> provided to address that risk.
>
> **Table 4: Table of Potential Risks and Controls**

+-----------------------------------+-----------------------------------+
| **Potential Risk**                | **Control**                       |
+-----------------------------------+-----------------------------------+
| Skin Trauma                       | Animal Testing and/ or Clinical   |
|                                   | Data                              |
| Blister Formation                 |                                   |
|                                   |                                   |
| Duragenic Patch Interaction       |                                   |
+-----------------------------------+-----------------------------------+
| Infection                         | Bench Testing & QSR (Sterility)   |
|                                   |                                   |
| Cellulitis                        |                                   |
|                                   |                                   |
| Toxic Shock Syndrome              |                                   |
|                                   |                                   |
| Sepsis                            |                                   |
+-----------------------------------+-----------------------------------+
| Sterility Compromised             | Animal Studies and Device         |
|                                   | Labeling (Sterility)              |
| Bacterial                         |                                   |
|                                   |                                   |
| Fungal                            |                                   |
+-----------------------------------+-----------------------------------+
| Physical Product Problems         | Bench Testing and Design Controls |
+-----------------------------------+-----------------------------------+
| Necrosis                          | Device Labeling,                  |
|                                   | Biocompatibility, Clinical Data   |
+-----------------------------------+-----------------------------------+
| Pain                              | Clinical Data                     |
+-----------------------------------+-----------------------------------+
| Inflammation/ Irritation and      | Biocompatibility, Animal Studies  |
| Swelling                          | and Device Labeling, Clinical     |
|                                   | Data                              |
+-----------------------------------+-----------------------------------+
| Allergic Reactions                | Biocompatibility, Device Labeling |
+-----------------------------------+-----------------------------------+
| Injury                            | Animal Studies/ Clinical Studies  |
|                                   | and Device Labeling               |
+-----------------------------------+-----------------------------------+

***Chapter 6, "Material and Performance Characterization":***

> This chapter would include the types of bench top testing, material
> characterization and manufacturing information that the Agency
> recommends for. The proposed chapter would read as follows:
>
> We recommend that you provide the information below to establish the
> material and performance characteristics of the device.

[]{.mark}

## Material Specification

> We recommend that you provide all material components of the device.
> Such information should identify the source and purity of each
> component. Such information may also be supplied by reference to a
> Master Access File(s), if the appropriate letter of cross reference is
> included. Submission of a Certificate(s) of Analysis (CoA) and/or a
> Materials Safety Data Sheet(s) (MSDS) will facilitate FDA's review of
> components/materials.
>
> **Product Characterization**
>
> We recommend that the product manufacturing process be briefly
> described and compared to that of the legally marketed predicate
> device.

We recommend that you provide the following product characterization
information regarding your dressing device containing a drug:

-   a complete description of all components and a detailed list of the
    amounts of each components contained in the dressing,

-   a profile of the ability of the device to provide a moist wound
    environment at the site of application, and a description of how it
    will do so

-   the biocompatibility profile of the device (biocompatibility testing
    should be conducted in accordance with International standard
    ISO-10993, Biological Evaluation of Medical Devices Part-1,
    evaluation and Testing and FDA General Memorandum G-95-1),

-   complete information regarding the drug component

> With regard to the drug(s) used as a component in the dressing, the
> following information should be provided:

-   identification of the drugs' purpose in the dressing

-   the claim associated with the drug (if applicable)

-   data using the finished sterilized device to support any claim
    associated with the drug

> With regard to labeling, the box label should identify all drugs
> present in the wound dressing as follows:

-   the name and form of the drug being used

-   the amount of drug present

## Final Product Specification 

> We recommend that you provide information about the relevant
> in-process and final product tests, including identification of the
> test method and time of testing during manufacture and the final
> product release specifications.
>
> Examples of final product release specifications include:

-   specific melting temperature

-   residual levels of manufacturing reagents

-   residual levels of heavy metals

-   pyrogen levels

-   sterility (Sterility Review Guidance K90-1; Final Guidance for
    Industry and FDA, www.fda.gov/cdrh/ode/guidance/361.html)

> We also recommend that you provide the rate of product absorption (if
> the device is made of any biodegradable materials). Such studies
> should be performed *in vivo* or in a manner expected to accurately
> predict product decomposition (e.g., in comparable cellular and
> proteolytic environments at 37^0^C). Please see Section 7 (**Animal
> Testing**) below for more details regarding this recommendation.
>
> **Shelf Life\
> \
> **We recommend that you provide both stability testing of the device
> and packaging testing to establish the shelf life (i.e., expiration
> date) for the labeling of your dressing device. Accelerated testing
> should be supported/validated by real-time shelf life testing. With
> regard to packaging testing, we recommend that you provide data for
> the final finished package for initial integrity and maintenance of
> integrity after selecting the appropriate materials and qualifying the
> package configuration. We recommend that you use test methods that are
> either validated or standardized.

***Chapter 7, "Animal Testing":***

This chapter discusses the animal testing the Agency would recommend.
The information proposed for inclusion into this chapter is as follows:

Animal testing may be needed if the biocompatibility testing has
indicated that the dressing may have delaying effect on the wound
closure. FDA recommends that your animal study include testing of a
legally marketed predicate device of similar components and manufacture
so that observations can be made as to the substantial equivalence of
the two dressings.

> The extent of animal testing needed will be dependent upon the
> differences between the proposed device and a legally marketed
> predicate device.

***Chapter 8, "Clinical Testing":***

> This chapter of the special controls guidance document discusses
> clinical data. The information proposed for this chapter is as
> follows:

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 wound
dressings containing drugs, FDA may recommend that you collect clinical
data for a dressing with:

-   new technology (i.e., technology different from that used in a
    legally marketed wound dressing); or

-   new indications for use for a wound dressing of the same type.

```{=html}
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```
-   FDA will always consider alternatives to clinical testing when the
    proposed alternatives are supported by an adequate scientific
    rationale. Please contact the Plastic and Reconstructive Surgery
    Devices Branch (PRSB) to discuss any clinical testing before
    initiating studies.

***Additional Labeling Considerations:***

> Labeling claims beyond the indications for use should be supported
> with data. We recommend that the labeling be accurate as the nature of
> the supporting data, e.g., bench testing supporting that the device is
> a bacterial barrier. The text of the labeling claim should be
> data-driven and be limited to a summary of the testing methods and
> results obtained. The labeling should not include hypothetical claims
> such as "may reduce infections." Broad, poorly defined claims for
> which it is difficult to provide supporting data should not be used.
> "Hypoallegenic and "sensitive skin" are examples of broad, poorly
> defined claims. For labeling that indicates that the device may act as
> an antibacterial barrier, it is expected that the claim would be the
> data demonstrating that the wound dressing has an antibacterial effect
> *in vitro*, and that the wound dressing is a barrier to the passage of
> the specific microorganisms tested. Specifically, we recommend that
> the testing demonstrate that if 1 million bacteria are placed on top
> of the dressing, none should come through to the agar in 24 hours. The
> antibacterial effectiveness of the device should be compared with
> positive and negative controls. In liquid culture, the titer should be
> reduced by at least 10^4^. Likewise, the claim should state that the
> supporting data were collected in bench testing.

**The Least Burdensome Provisions of FDAMA:**

A central purpose of the Food and Drug Administration Modernization Act
of 1997 (FDAMA) is "to ensure the timely availability of safe and
effective new devices that will benefit the public and to ensure that
our Nation continue to lead the world in new device innovation and
development. Congress' goal was to streamline the regulatory process
(i.e., reduce burden) to improve patient access to drugs and devices
that could benefit the public.\
\
One of the concepts central to this "least burdensome" approach to the
regulation of medical devices is to review devices at the Class level
(Class I, Class II, Class III) where they will receive an appropriate
level of oversight in accordance with what is known about the safety and
effectiveness of the device type. Since wound dressings with drugs have
been in use for approximately 100 years, the Agency believes that they
can be appropriately regulated at the Class II, Special Controls,
regulatory level because the assessment of their effectiveness and the
known complications are well understood due to the many years of
experience in their use. More than just risk is taken into account when
devices are classified. An understanding of the methods to assess safety
and effectiveness is a central factor in the classification of medical
devices. Other Class II devices that are considered to have high risks
associated with their use are dura replacements, surgical meshes and
sutures.

The Guidance Document: *The Least Burdensome Provisions of the FDA
Modernization Act of 1997: Concept and Principles; Final guidance for
FDA and Industry*, is provided as a reference for your convenience,
located in the appendix (Tab 11).

Your panel package includes information on the classification of medical
devices in the appendix (Tab 1). The slides with an asterisk pertain to
the classification of unclassified pre-amendment devices and are
relevant to the classification of wound dressings with drugs. This
Appendix also contains the questionnaire that you will vote on as part
of your recommendation on the classification of this device.

[\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
\_\_\_\_]{.underline}

Sam Arepalli, Ph.D. Date

FDA/CDRH/ODE/DGRND/PRSB

**TAB 7**

Tab 7 of the material sent to the panel members consists of literature
articles referred to in each of the six previous memos. These are
publicly available.

**TAB 8**

**[Classification Topics]{.underline}**

1.  Please discuss the proposed classification for all of the devices
    presented in this package to include bone wax, medical maggots,
    medicinal leeches, tissue expanders, and wound dressing with drugs.

2.  Please discuss the possible risks to health that may be associated
    with each device.

3.  Please discuss whether the special controls identified for the FDA
    Guidance Document are adequate.

**TAB 9**

Tab 9 is simply a copy of the standard questionnaire each panel member
fills out during the recommendation process. This will be displayed as
it is filled in during the panel meeting.

**TAB 10**

Tab 10 is a sample guidance document presented to the panel. It is
entitled: "*Class II Special Controls guidance Document: Surgical
Sutures; Draft Guidance for Industry and FDA"* This is available on the
FDA Web Site at the following web address:
<http://www.fda.gov/cdrh/ode/guidance/1387.html>

**TAB 11**

Tab 11 is a guidance document presented to the panel to explain the
"Least Burdensome" concept of the FDA Modernization Act of 1997. It is
entitled: "*The Least Burdensome Provisions of the FDA Modernization Act
of 1997: Concept and Principles; Final Guidance for FDA and Industry"*
This is available on the FDA Web Site at the following web address:
<http://www.fda.gov/cdrh/ode/guidance/1332.html>

[^1]:
    > 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.

[^2]: 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.