Dear Panel Member,

Thank you for agreeing to attend the July 24 meeting of the General and
Plastic Surgery Devices Advisory Committee (Panel) and taking part in a
vote to either recommend or not recommend reclassification of the
absorbable hemostatic agent and dressing devices from regulatory Class
III to Class II.

The agency's rationale for recommending that this device be down
classified are summarized as follows:

-   We have years of experience regulating this device category

-   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.

-   We have successfully down classified a number of similar device
    categories, and provide a suture guidance special control as a
    specific example.

-   Down classification meets the FDA mandate to apply the "least
    burdensome" approach to regulating medical devices

-   At a Panel meeting last year on this topic, the Panel indicated they
    would like to review the content of the draft special control for
    absorbable hemostatic agents, and this information is provided now
    for your review in this memo.

The absorbable hemostatic agent and dressing devices were regulated as
drugs from the time the first ones, Gelfoam and Oxycel, were introduced
into the market place in the early 1940s. A number of devices, including
the absorbable hemostatic agent and dressing devices, were transferred
to device regulations shortly after President Ford signed the Medical
Device Amendments to the Food, Drug and Cosmetic Act in 1976. All of
these "transitional" devices were regulated as Class III medical
devices. Some of these devices, e.g., sutures, were reclassified to
Class II when enough safety and effectiveness information was obtained
in order to support such a change in class.

The Agency's rationale for recommending this change in regulatory class
is based on the long history of safe and effective use of these devices
over the past 60 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.

A search of the small number of adverse event reports in the medical
literature and in the FDA's Medical Device Reporting System has
identified the most common adverse reactions to the absorbable
hemostatic agent and dressing devices. These are discussed below as well
as the recommended method of amelioration.

The most recent amendment to the FD&C Act, the Medical Device User Fee
Modernization Act (MDUFMA), passed in 2002, directed the Agency to
regulate medical devices in the "least burdensome" manner possible based
on the available safety and effectiveness information. It is with this
in mind that we are requesting that you vote to reclassify the
absorbable hemostatic agent and dressing devices into regulatory Class
II.

**Introduction to Regulatory History of Absorbable Hemostatic Agents and
Dressings:**

Absorbable hemostatic agent and dressing devices were regulated as drugs
and required a New Drug Application (NDA) for marketing approval up
until 1976. At that time these transitional devices were transferred to
device regulations in the Center for Devices and Radiological Health.
All transitional devices were automatically classified as Class III
medical devices. The 1976 Device Amendments as amended by the Safe
Medical Device Act (SMDA) of 1990, the FDA Modernization Act (FDAMA) of
1997, and MDUFMA provide regulations for the reclassification and
regulation of medical devices intended for human use. FDA may elect to
reclassify a medical device, including a Class III medical device, into
a lower 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, premarket 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, postmarket 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 devices 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 many 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.

The absorbable hemostatic agents and dressings approved via the PMA or
NDA regulatory process to date contain porcine or bovine gelatin, bovine
collagen, or regenerated oxidized cellulose.

FDA has regulated absorbable hemostatic agents under regulation number
21 CFR §878.4490, "Absorbable hemostatic agent and dressing". These
devices are defined as "a device intended to produce hemostasis by
accelerating the clotting process of blood. It is absorbable. As of May
28, 1976, it has required an approval under section 515 of the act to
allow commercial distribution of an absorbable hemostatic agent." Note:
while the name of the device classification includes "Dressing," we have
interpreted this absorbable device to be surgical hemostatic agents.
Wound dressings are topical and some contain an indication for
hemostasis and have been regulated as 510(k)s for many years.
Consequently, we are proposing to modify the name of hemostatic agents
to clarify that topical dressings are not included in the device
classification of an absorbable hemostatic agent\...

Since 1976, CDRH has approved ten absorbable hemostatic agents. A number
of hemostatic agents were approved through the new drug process and then
transferred to CDRH for regulation after 1976. Most of these devices
should be familiar to you. Table 1 identifies devices included in the
absorbable hemostatic agent device group.

The proposal for reclassification of the absorbable hemostatic agent was
presented to the General and Plastic Surgery Devices Panel on July 8,
2002. During that meeting the panel voted to table any recommendation on
the reclassification of these devices until the panel had the
opportunity to review the proposed special controls guidance document.
At this meeting, the Agency plans to present to the panel the
information that will be included in such a special controls guidance
document for the absorbable hemostatic agent and dressing devices.

**Table 1**

**Absorbable Hemostatic Agents Approved Through PMA or NDA\***

+----------+---------------+---------+-----------------+-------------+
| **P      | **Present     | **Appl  | **Ch            | **Approval  |
| roduct** | Application   | ication | aracteristics** | Date**      |
|          | Holder**      | Numbe   |                 |             |
|          |               | r\*\*** |                 |             |
+----------+---------------+---------+-----------------+-------------+
| **G      | Pharmacia and | N18286  | Porcine Gelatin | Available   |
| elfoam** | Upjohn        |         | molded into a   | 1945        |
|          |               |         | sponge          |             |
|          |               |         |                 | July 8,     |
|          |               |         |                 | 1983        |
+----------+---------------+---------+-----------------+-------------+
| **Oxyc   | Becton        | N5798   | Sponge made of  | September   |
| el\*\*** | Dickinson     |         | Oxidized        | 12, 1945    |
|          |               |         | Cellulose       |             |
+----------+---------------+---------+-----------------+-------------+
| **Su     | Ethicon       | N12159  | Sponge made of  | October 14, |
| rgicel** |               |         | Regenerated     | 1960        |
|          |               |         | Oxidized        |             |
|          |               |         | Cellulose       |             |
+----------+---------------+---------+-----------------+-------------+
| **A      | Davol         | N17600  | Bovine Collagen | August 26,  |
| vitene** |               | and     |                 | 1976        |
|          |               | P800002 |                 |             |
|          |               |         |                 | October 24, |
|          |               |         |                 | 1980        |
+----------+---------------+---------+-----------------+-------------+
| **Col    | Integra       | P810006 | Bovine Collagen | December    |
| lastat** | LifeSciences  |         |                 | 10, 1981    |
+----------+---------------+---------+-----------------+-------------+
| *        | Superstat     | P810040 | Bovine Collagen | January 29, |
| *Superst |               |         |                 | 1982        |
| at\*\*** |               |         |                 |             |
+----------+---------------+---------+-----------------+-------------+
| **       | Ethicon       | P830079 | Bovine Collagen | October 10, |
| Instat** |               |         |                 | 1985        |
+----------+---------------+---------+-----------------+-------------+
| **       | Integra       | P850010 | Bovine Collagen | November 8, |
| Helistat | LifeSciences  |         |                 | 1985        |
| He       |               |         |                 |             |
| litene** |               |         |                 |             |
+----------+---------------+---------+-----------------+-------------+
| *        | Datascope     | P850023 | Bovine Collagen | May 27,     |
| *Hemopad |               |         |                 | 1986        |
| N        |               |         |                 |             |
| ovacol** |               |         |                 |             |
+----------+---------------+---------+-----------------+-------------+
| **Actifo | Coletica      | P930030 | Bovine Collagen | August 15,  |
| am\*\*** |               |         |                 | 1995        |
+----------+---------------+---------+-----------------+-------------+
| **S      | Ethicon       | P990004 | Porcine Gelatin | September   |
| urgifoam |               |         | sponge          | 30, 1999    |
| Spon     |               |         |                 |             |
| gistan** |               |         |                 |             |
+----------+---------------+---------+-----------------+-------------+
| *        | Baxter        | P990009 | Flowable Bovine | December 8, |
| *FloSeal | Healthcare    |         | Gelatin Matrix  | 1999        |
| Hemostat |               |         | and Licensed    |             |
| \*\*\*** |               |         | Bovine Thrombin |             |
+----------+---------------+---------+-----------------+-------------+
| **       | Cohesion      | P990030 | Flowable Bovine | June 13,    |
| CoStasis | Technologies  |         | Collagen and    | 2000        |
| \*\*\*** |               |         | Licensed Bovine |             |
|          |               |         | Thrombin        |             |
|          |               |         | combined with   |             |
|          |               |         | Autologous      |             |
|          |               |         | Platelets       |             |
+----------+---------------+---------+-----------------+-------------+

\* Application Numbers starting with "N" indicate devices submitted to
the Center for Drugs (CDER) and Numbers starting with "P" are devices
submitted to the Center for Devices (CDRH). Some of the applications
with numbers starting with N were approved in CDRH even though they were
submitted to CDER.

\*\* Not sold in the US at this time.

\*\*\* A Combination Product, comprised of a device and a biologic
component combined to produce a single entity.

# 

# Risks to Health

FDA regulates many other medical devices manufactured from similar
animal source materials as Class III, Class II, and unclassified
devices. For example, the femoral artery sealing device, which may have
a porcine or bovine collagen or gelatin component, is regulated as a
Class III medical device. Collagen surgical mesh, gelatin coated
surgical mesh, collagen suture, collagen dura replacement, and other
collagen/gelatin-containing implants are regulated as Class II medical
devices. Other collagen/gelatin-containing medical devices, such as the
collagen-based wound dressings, are currently regulated as unclassified
medical devices.

In order to summarize the potential risks associated with the use of the
absorbable hemostatic agents, 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, 2003) for the absorbable hemostatic agents received
by the Agency are summarized in Table 2.

**Table 2: Adverse Events Reported**

  ------------------- ----------------- ----------------- ----------------
  **Adverse Event**   **Absorbable      **Absorbable      **Total Events**
                      Hemostatic Agents Hemostatic Agents 
                      without           with Thrombin**   
                      Thrombin**                          

  **Device failure    1                 8                 9
  (continued bleeding                                     
  observed)**                                             

  **Device deployment 0                 7                 7
  failure**                                               

  **Abdominal         2                 4                 6
  Infection**                                             

  **Sinus Infection** 1                 5                 6

  **Paralysis         5                 0                 5
  following off-label                                     
  placement in                                            
  vertebral column**                                      

  **Infection         5                 0                 5
  following tooth                                         
  extraction**                                            

  **Granuloma**       2                 0                 2

  **Abscess**         2                 0                 2

  **Foreign Body      1                 1                 2
  Reaction**                                              

  **Allergic          0                 2                 2
  Reaction**                                              

  **Interference with 0                 2                 2
  wound healing**                                         

  **Respiratory       0                 2                 2
  Difficulty**                                            

  **Bowel             1                 0                 1
  Obstruction**                                           

  **Hematoma**        1                 0                 1

  **Intermittent      0                 1                 1
  ischemia**                                              

  **Stroke**          0                 1                 1

  **Seroma**          0                 1                 1

  **Tissue Necrosis** 1                 0                 1

  **Couldn't figure   1                 0                 1
  out how to store**                                      

  **Erythema**        0                 1                 1

  **Edema**           0                 1                 1

  **Total**           23                36                59
  ------------------- ----------------- ----------------- ----------------

The following literature articles are indicative of the published
literature on absorbable hemostatic agents. These articles discuss
absorbable hemostatic agents and also describe some potential risks of
using these devices. Copies of these articles are provided in Tab 4.

1.  Arand AG and Sawaya R. Intraoperative chemical hemostasis in
    neurosurgery. Neurosurgery 18(2): 223-33 (1986).

2.  Bloom AL and Thomas DP. Eds. "*Haemostasis and Thrombosis*"
    Churchill Livingstone (London, England, 1987) pp. 614-5.

3.  Browder IW and Litwin MS. Use of absorbable collagen for hemostasis
    in general surgical patients. Am. Surg. 52(9): 492-4 (1986).

4.  DeLustro F, Dasch J, Keefe J and Ellingsworth L. Immune responses to
    allogeneic and xenogeneic implants of collagen and collagen
    derivatives. Clin. Orthop. 260: 263-79 (1990).

5.  Evans BE. Local hemostatic agents. NY State Dent. J. 47(4): 109-14
    (1977).

6.  Light RE. Hemostasis in Neurosurgery. J. Neurosurgery 2(5): 414-34
    (1945).

7.  Light RE and Prentice HZ. Surgical investigation of a new absorbable
    sponge derived from gelatin for use in hemostasis. J. Neurosurgery
    2(5): 435-55 (1945).

8.  Lindstrom PA. Complications from the use of absorbable hemostatic
    sponges. AMA Arch. Surg. 73: 133-41 (1956).

9.  Schwartz SI. Ed. "*Principles of Surgery, 7^th^ Edition*"
    McGraw-Hill (New York, 1999) pp. 92-93.

These articles, as well as others, and absorbable hemostatic agent
labels were reviewed in order to compile the risks identified in Table
3. Tables 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 failure  Animal Studies and/or
                                               Clinical Data

  Hematoma as a result of continued bleeding   Animal Studies and Device
  following device application                 Labeling

  Potentiation of bacterial growth leading to  Animal Studies and Device
  increased infections and Fever               Labeling

  Wound dehiscence due to device interposition Device Labeling
  at the wound edge                            

  Inflammation and/or edema due to foreign     Device Labeling and
  body reaction                                biocompatibility

  Adhesion formation                           Animal Studies

  Failure to be absorbed                       Bench Testing and Animal
                                               Studies

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

  Aspiration into transfusion filters may      Device Labeling
  activate coagulation *in vitro*              

  Use of antiplatelet drug therapy, systemic   Device Labeling
  heparinization and cardiopulmonary bypass    
  may increase risk for hemostatic agent       
  failure                                      

  Use of the hemostatic agent in closed spaces Device Labeling
  may result in pressure causing nerve damage  
  or tissue necrosis                           

  Accidental injection into the intravascular  Device Labeling
  space may result in embolization             

  Paralysis due to swelling of the device and  Device Labeling
  exertion of pressure onto nerves             

  Infection due to improper sterilization      Bench Testing and QSR
  -------------------------------------------- --------------------------

**Proposed Reclassification:**

The Agency is proposing that the absorbable hemostatic agents may be
reclassified to a lower classification (Class II, special controls).
These devices have been regulated by CDRH since 1976, and previous to
that were regulated as drugs since the 1940s when both Gelfoam and
Oxycel were introduced into the marketplace. During this time a great
deal of clinical and preclinical data has been collected that indicate
that these devices are safe and effective in controlling bleeding when
used in accordance with their approved labeling. The data reported in
the literature and medical device reporting have identified the greatest
potential risks to the patients. These are identified in Table 2. The
Agency feels that all of these potential risks can be addressed via
special controls in the form of a guidance document. The devices within
this category are currently manufactured from the following materials:

*Absorbable Gelatin Sponge:* The gelatin sponge is an absorbable
material created from porcine gelatin through which nitrogen has been
bubbled in order to produce a porous device. This method was first
introduced by Correll and Wise in 1945. The sponge has no intrinsic
hemostatic action but induces hemostasis through its intensely porous
structure, which enables it to absorb 45 times its weight in blood. As
it fills with blood the platelets come into close contact and begin to
collide initiating the clotting cascade.

*Oxidized Cellulose:* Oxidized cellulose is a fabric material that is
obtained by the oxidation of cotton, gauze, or other cellulose fabric
using nitrous oxide to achieve oxidation. The process was first
described by Yackel and Kenyon of Eastman Kodak Laboratories in 1942.
This reaction converts certain of the hydroxyl radicals to carboxyl
groups and makes the material soluble at physiological conditions. The
low pH of the cellulosic acid within the device has caustic properties
that lead to hemostasis via the initial denaturation of blood proteins.

*Regenerated Oxidized Cellulose:* Similar to oxidized cellulose, but
cellulose is first dissolved and then extruded as a continuous fiber.
The fabric made from the fiber is very uniform in chemical composition
and its oxidation is more closely regulated. This uniform oxidation
results in less variation in absorbability of the material. The
regenerated oxidized cellulose induces hemostasis in a manner identical
to oxidized cellulose.

*Microfibrillar Collagen:* Microfibrillar collagen is a water-insoluble,
partial hydrochloric acid amino salt of natural collagen in the form of
fibers containing microcrystals prepared from purified bovine dermal
collagen. Microfibrillar collagen acts primarily by reaction with
platelets. Platelets attach to specific sites on collagen and
degranulate initiating the hemostatic cascade leading to a fibrin clot.

**Proposed Identification for Absorbable Hemostatic Agents for the Code
of Federal Regulations:**

**PRESENT CFR LISTING for ABSORBABLE HEMOSTATIC AGENT and DRESSING**

(a) *Identification.* An absorbable hemostatic agent is a device
    intended to produce hemostasis by accelerating the clotting process
    of blood. It is absorbable.

(b) *Classification.* Class III.

(c) *Date PMA or notice of completion of a PDP is required.* As of May
    28, 1976, an approval under section 515 of the act is required
    before this device may be commercially distributed. See § 878.3.

**PROPOSED IDENTIFICATION for THE ABSORBABLE HEMOSTATIC AGENT, SURGICAL
(note new name):**

**§ 878.4490 -- Absorbable hemostatic agent, surgical**

(a) *Identification*. An absorbable hemostatic agent, surgical is an
    absorbable device intended to produce hemostasis by accelerating the
    clotting process of blood during surgical procedures.

(b) *Classification*.

> Class II (special controls). The special control for the class II
> device is FDA's "Class II Special Controls Guidance Document:
> Absorbable Hemostatic Agent, Surgical Device; Draft Guidance for
> Industry and FDA."

**Summary of July 8, 2003 General and Plastic Surgery Devices (GPS)
Panel Meeting:**

Last year this Panel met to vote on this reclassification proposal. The
GPS panel members heard from representatives of the manufacturers
(Johnson & Johnson Wound Management Worldwide, Ferrosan A/S, and Integra
LifeSciences) of absorbable hemostatic agents and from the FDA. The
industry representatives and the FDA provided information attesting to
the safe and effective use of the absorbable hemostatic agents for over
60 years. After these presentations, members of GPS panel discussed the
proposed reclassification of the absorbable hemostatic agents from Class
III to Class II. The consensus of opinion of the panel was that the
device was appropriate for reclassification to Class II, but that they
did not feel comfortable recommending reclassification without reviewing
the proposed special control, a guidance document, developed to assure
the continued safety and effectiveness of these devices. Therefore, the
panel voted 4 to 3 to table the vote on the proposed reclassification of
absorbable hemostatic agents.

At the panel meeting, representatives of the manufacturers of some
absorbable hemostatic agents pointed out that the manufacture of their
device required careful purification of native fibers, controlled
oxidation reactions, defined chemistry, dehydration, etc. The industry's
central argument was that a special controls guidance document might be
insufficient to address the complex nature of the processing that is
involved in the manufacture of this type of device. FDA agrees that the
manufacture of these devices can be complex, however, FDA believes that
we understand how to evaluate the performance of the finished device in
order to evaluate whether they are safe and effective.

**Special Controls Guidance Document:**

When the Office of Device Evaluation (ODE) reclassifies a medical device
from regulatory Class III to regulatory Class II, such reclassifications
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. The guidance document: "*Class II Special Controls
Guidance Document: Surgical Sutures; Draft Guidance for Industry and
FDA"*, issued on June 3, 2003, is provided 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 Class II special controls
guidance document for the absorbable surgical hemostatic agent devices
would be very similar to the example special controls guidance document
provided with the exception that specific device information would be
different. The suture special control is also relevant because when FDA
reclassified surgical sutures from Class III to Class II, one of the
concerns mentioned by the industry was that suture manufacturing was
technically complex. FDA agreed but felt that the performance
characteristics needed to evaluate the safety and effectiveness of the
finished sutures were well understood and could, therefore, be
appropriately regulated as Class II.

While the agency has not provided you with a copy of a draft proposed
special controls guidance document for absorbable hemostatic agents,
this memo 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 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 11 of a special controls guidance
document for the absorbable surgical hemostatic agents. 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.

> **Chapter 5, "Risks to Health":**
>
> This chapter would include information quite similar to the table
> above, which discusses the risks to health associated with the use of
> the absorbable surgical hemostatic agents. 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 absorbable hemostatic agent 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. 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 device failure Sections 6, 7, and 8

  Hematoma from continued bleeding following  Sections 7, 8, and 11
  device application                          

  Potentiation of bacterial growth leading to Sections 7, 9, and 11
  increased infections and Fever              

  Wound dehiscence at the wound edge          Section 11

  Inflammation and/or edema due to foreign    Sections 7, 10, and 11
  body reaction                               

  Adhesion formation                          Section 7

  Failure to be absorbed                      Sections 6, 7, and 10

  Reduced strength of methylmethacrylate      Sections 7 and 11
  adhesion when used to attach prosthetic     
  devices to bone surfaces                    

  Aspiration into blood transfusion filters   Section 11
  may activate coagulation inside the         
  filtering device                            

  Concomitant antiplatelet drug therapy,      Sections 7 and 11
  systemic heparinization and cardiopulmonary 
  bypass may increase risk for hemostatic     
  agent failure                               

  Application in closed spaces may exert      Section 11
  pressure causing nerve damage or tissue     
  necrosis                                    

  Accidental injection into the intravascular Section 11
  space may result in embolization            

  Paralysis due to swelling of the device and Section 11
  exertion of pressure onto nerves            

  Infection due to improper sterilization     Sections 6 and 9
  ------------------------------------------- ---------------------------

> **Chapter 6, "Material and Performance Characterization":**
>
> This chapter would include the types of bench top, material
> characterization and manufacturing information that the Agency would
> be looking for. The proposed chapter would read as follows:
>
> We recommend that the information below be performed to establish the
> material and performance characteristics of the device.
>
> []{.mark}
>
> ***Material Information\
> ***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 File(s), if the appropriate letter of cross reference is
> included. Submission of a Certificate(s) of Analysis and/or a
> Materials Safety Data Sheet(s) can also greatly simplify review of
> components.
>
> If collagen or other animal-derived material is a device component, we
> recommend that you also provide the following information:

-   The species and tissue from which the animal material was derived,
    including the specific type of collagen or other material used.

-   How is the herd's health maintained and monitored? For example:

    -   Is the herd closed?

    -   What vaccinations are standard for the herd (e.g., focus on live
        modified viruses)?

    -   Are veterinarian inspections performed and if so how frequently?

    -   What is the composition of the animal feed?

    -   Is the abattoir USDA approved or inspected?

    -   If the animal material is of bovine origin, certification that
        the herd is from a bovine spongiform encephalopathy-free
        country.

-   How is each animal's health maintained and monitored? For example:

    -   What is the age of the animal at sacrifice?

    -   Are pre- and/or post-mortem inspections performed?

    -   What tests are performed to determine that the material is
        acceptable for further processing or pooling with material from
        other animals?

> If the device contains synthetic (e.g., polymeric) components, we
> recommend that you provide the concentration in the final device of
> any component (e.g., organic solvents, heavy metals, cross-linking
> reagents) that is potentially toxic, carcinogenic or immunogenic.
>
> ***Manufacturing Information\
> ***We recommend that the device manufacturing process be briefly
> described and compared to the standard methods for this device. Any
> innovations or deviations from the accepted methods must be supported
> with data that justify the modifications since any modifications from
> standard techniques could effect time to hemostasis, absorption
> properties or other important characteristic of the device.
>
> We recommend that you provide the final device release specification
> for relevant in-process and final device tests, including
> identification of the test method and time of testing during
> manufacture. Examples of final device release specifications include:

-   Specific amino acid content for protein devices

-   Residual levels of manufacturing reagents

-   Residual levels of heavy metals

-   Pyrogen levels, and

-   Sterility.

> ***\
> ***
>
> ***Final Device Information***
>
> We recommend that you provide the following information regarding your
> final absorbable hemostatic agent:

-   Cross-linking agent material identification and toxicity

-   Initial cross-linking agent concentration and any residual
    concentration

-   The time to complete device absorption determined in animal studies.
    Animal studies should be performed in a manner expected to
    accurately predict device decomposition (e.g., in comparable
    cellular and proteolytic environments at 37°C).

> ***Shelf Life Information\
> ***FDA recommends that you provide shelf life data supporting an
> expiration date for the labeling of your absorbable hemostatic agent.
> Shelf life testing should consist of both stability testing of the
> agent and packaging testing.
>
> We recommend that you collect stability data from at least three
> production lots. The stability data should include the critical
> parameters of the absorbable hemostatic agent that are required to
> ensure it will perform consistently during its entire shelf life.
>
> 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.\
> \
> Accelerated testing should be supported/validated by real-time shelf
> life testing. The appropriateness of accelerated stability data is
> determined by device composition. The value of accelerated stability
> test data relies on identical decomposition mechanisms at both
> standard and elevated temperatures. When device failure/decomposition
> occurs by different mechanisms at the standard and elevated
> temperatures of accelerated stability testing (e.g., loss of sterility
> at 25°C versus protein denaturation at 50°C), accelerated stability
> test data will not support claims for device stability.
>
> **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:
>
> FDA recommends that you provide animal studies modeling each surgical
> application for which the absorbable hemostatic agent is to be
> indicated. For example, for general surgical use, we recommend that
> the animal testing include arteriolar, venous and capillary bleeding
> from various tissues and organs. For the arterial bleeding, we
> recommend that you provide specific data to support this indication.
>
> FDA recommends that your animal study evaluates the time to
> hemostasis, time to resorption of the hemostatic agent, and any
> complications. The complications monitored should include infections,
> hematomas, coagulopathies, increased wound healing times, etc.
>
> FDA also recommends that your animal study include testing of an
> approved/cleared 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.
>
> **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 absorbable hemostatic agent devices, FDA may recommend that
> you collect clinical data for an absorbable hemostatic agent device
> with:

-   New technology, i.e., technology different from that used in legally
    marketed absorbable hemostatic agent device); or

-   Indications for use dissimilar from an absorbable hemostatic agent
    device of the same type.

> FDA will always consider alternatives to clinical testing when the
> proposed alternatives are supported by an adequate scientific
> rationale.
>
> Absorbable hemostatic agents are primarily applied during surgical
> procedures in order to control bleeding that is not readily controlled
> via conventional means such as cautery or ligation. At other times, an
> absorbable hemostatic agent may be applied due to the inaccessibility
> of a site to conventional hemostatic methods. Accordingly, FDA
> recommends that a clinical study address the following:

-   A study should be designed to compare the safety and effectiveness
    of the new device to a legally marketed predicate device. In most
    cases, such comparisons should be made between absorbable hemostatic
    agents manufactured from similar materials and with similar
    indications for use.

-   A study should be conducted at enough institutions to assure that
    the observations made regarding the safety and effectiveness of the
    devices will be significant in spite of technical and procedural
    differences likely to be encountered when the device is marketed.

-   Patients should be followed for a reasonable length of time to
    assess any after effects of device use.

-   Safety and effectiveness should be demonstrated for each surgical
    specialty for which the device is to be indicated beyond the general
    surgery indication. As in the animal studies, device absorption and
    or migration are likely to vary from site to site and specific data
    should be provided.

-   The primary effectiveness endpoint for the clinical study should
    assess the device's ability to achieve hemostasis in a reasonable
    amount of time.

-   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.

> The Plastic and Reconstructive Surgery Devices Branch is available to
> discuss any questions you may have about clinical studies and
> alternatives.
>
> 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. FDA has determined that the
> absorbable hemostatic agent device addressed by this guidance document
> is a significant risk device as defined in 21 CFR 812.3(m)(4). In
> addition to the requirement of having an FDA-approved IDE, sponsors of
> such trials must comply with the regulations governing institutional
> review boards (21 CFR Part 56) and informed consent (21 CFR Part 50).
>
> After FDA determines that the device is substantially equivalent,
> clinical studies conducted in accordance with the indications reviewed
> in the 510(k), including clinical design validation studies conducted
> in accordance with the quality systems regulation, are exempt from the
> IDE requirements. However, such studies must be performed in
> conformance with 21 CFR 56 and 21 CFR 50.
>
> **Chapter 9, "Sterility":**
>
> This is a chapter that is fairly boilerplate for most medical devices.
> The information to be included in this chapter 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^.
>
> **Chapter 10, Biocompatibility:**
>
> This is another chapter where the language and content is virtually
> identical from guidance document to guidance document. The proposed
> information to be placed into this chapter 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 biocompatibility testing.
>
> **Chapter 11, Labeling:**
>
> This last chapter of the special controls guidance document gives
> recommendations of the general content of the labeling for a medical
> device. I am providing a specific example of the information ODE
> recommends for the labeling of an absorbable surgical hemostatic agent
> in the labeling for the Surgifoam device attached to this memo. The
> proposed information for this chapter 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 807.87(e).
>
> []{.mark}
>
> []{.mark}
>
> **Prescription Use:**
>
> In accordance with 21 CFR 801.109, this device must bear the following
> caution statement: \"Caution: Federal law restricts this device to
> sale by or on the order of a physician.\"
>
> **Instructions for Use:**
>
> Instructions for Use" should include adequate information regarding
> the contraindications, warnings, and precautions in order to address
> the identified risks to health and a clear explanation of the device
> technological features and how it is to be used.

**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 absorbable hemostatic agents
have been on the market since the 1940s, the Agency believes that they
can be appropriately regulated at the Class II, Special Controls,
regulatory level because how to assess their effectiveness and what the
known complications are, from the use of these devices, is well
understood. 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. Sutures were Class III transitional devices that were
reclassified in the early 1990s.

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.

David Krause, PhD

Biologist/Expert Reviewer

Plastic and Reconstructive Surgery Devices Branch

Division of General, Restorative, and Neurological Devices