***Proposed***

**Summary of Safety and Effectiveness**

**CryoLife , Inc. BioGlue^®^ Surgical Adhesive**

# General Information

> Device Generic Name: Surgical Adhesive
>
> Device Trade Name: BioGlue^®^ Surgical Adhesive
>
> (BioGlue^®^)
>
> Applicant's Name and Address CryoLife, Inc.
>
> 1655 Roberts Boulevard, NW
>
> Kennesaw, Georgia 30144
>
> Premarket Approval (PMA) Number: P010003
>
> Date of PMA: January 31, 2001
>
> Date of PMA Preapproval Inspection April 16-26, 2001
>
> Date of Panel Recommendation: September 11, 2001
>
> Date of Notice of Approval to Applicant:

# Indications For Use

> > BioGlue^^ Surgical Adhesive is indicated for use as an adjunct to
> > standard methods of cardiac and vascular repair such as sutures (or
> > staples) to provide hemostasis.

# Device Description

> > BioGlue Surgical Adhesive (BioGlue), manufactured by CryoLife, Inc.,
> > Kennesaw, GA, may be used prophylactically or after a leak is
> > detected to seal and reinforce anastomoses in cardiac and vascular
> > surgical repairs.
>
> > BioGlue is a two-component surgical adhesive composed of purified
> > bovine serum albumin (BSA) and glutaraldehyde. The BSA is derived
> > from serum obtained from cattle exclusively from bovine spongiform
> > encephalopathy (BSE) free countries and undergoes processing that
> > removes/inactivates viruses. The solutions are dispensed by a
> > controlled delivery system, composed of a reusable delivery device,
> > applicator tips, and applicator tip extenders. Once dispensed, the
> > adhesive solutions (in a predefined ratio) are thoroughly mixed *in
> > vitro* through the tortuous path of the applicator tip where
> > cross-linking starts to occur. The glutaraldehyde molecules
> > covalently bond (cross-link) the BSA molecules to each other and,
> > upon application, to the tissue proteins at the anastomotic repair
> > site thereby creating a flexible mechanical seal, independent of the
> > body's clotting mechanism. The device-mediated application is
> > designed to provide reproducible mixing of the components *in vitro*
> > and higher bonding strength than manual on-site (*in situ*) mixing
> > and application. BioGlue begins to set up within 20 to 30 seconds
> > and reaches its bonding strength within 2 minutes. BioGlue also
> > adheres to synthetic graft materials via mechanical interlocks
> > within the interstices of the graft matrix.

# Contraindications, Warnings and Precautions

## Contraindications

-   Do not use in patients with known allergies to materials of bovine
    > origin.

-   Not for intravascular use.

-   Not for cerebrovascular repair.

## Warnings

-   BioGlue Surgical Adhesive is not intended as a substitute for
    > sutures or staples.

-   Do not expose tissue to the device if it may be adversely affected
    > by contact with the device, e.g., aortic valve cusps and
    > intra-cardiac structures.

-   Do not allow device in either the uncured or polymerized form to
    > contact circulating blood flow.

-   Avoid exposing any nerves to surgical adhesive.

-   Avoid contact with skin or other tissue not intended for
    > application.

-   Glutaraldehyde treated tissue has an enhanced propensity for
    > mineralization. Laboratory experiments indicate that unreacted
    > glutaraldehyde may have mutagenic effects.

-   Unreacted glutaraldehyde may cause irritation to eye, nose, throat,
    > or skin; induce respiratory distress; and local tissue necrosis.
    > Prolonged exposure to unreacted glutaraldehyde may cause a central
    > nervous system or cardiac pathology. Operators using the device
    > should ensure that staff are adequately risk protected.

-   BioGlue should not be used in the presence of infection and should
    > be used with caution in contaminated areas of the body.

-   Exposure to bovine serum albumin may cause a reaction such as
    > swelling or edema at the application site.

-   BioGlue Surgical Adhesive contains a material of animal origin,
    > which therefore may be capable of transmitting infectious agents.

## Precautions

-   It is recommended that surgical gloves, sterile gauze pads/towels,
    > and surgical instruments be maintained moist to minimize the
    > potential for BioGlue inadvertently adhering to these surfaces.

-   Wear gloves, mask, protective clothing, and safety glasses. If
    > contact with solutions occurs, flush affected areas immediately
    > with water and seek medical attention.

-   BioGlue Surgical Adhesive solutions cartridges, applicator tips, and
    > applicator tip extenders are for single patient use only. Do not
    > re-sterilize.

-   Do not use if packages have been opened or damaged.

-   Do not prime delivery device until ready for immediate use.
    > Premature priming may cause the applicator tip to become
    > obstructed with polymerized adhesive.

-   Take care not to spill solutions out of the cartridge.

-   Do not compress the handle of the adhesive delivery device while
    > attaching the cartridge to the delivery device.

-   Attempting to apply the adhesive in a surgical field that is too wet
    > may result in poor adherence.

-   Ensure priming material does not come into contact with the surgical
    > site.

-   BioGlue Surgical Adhesive sets up immediately. Priming must occur
    > quickly, followed immediately by the application of adhesive.
    > Pausing between priming and application can cause set-up of
    > adhesive within the applicator tip.

-   If the BioGlue Surgical Adhesive adheres to an undesired location,
    > allow the adhesive to polymerize and then attempt to gently
    > dissect the adhesive away from the affected area with forceps and
    > scissors. Do not attempt to peel away the BioGlue Surgical
    > Adhesive as this could result in tissue damage at the application
    > site.

# Alternative Practices and Procedures

> > Conventional procedures used to control bleeding include the use of
> > direct pressure, sutures, pledgets, and/or electrocautery.
> > Absorbable hemostatic agents such as bovine gelatin powder and
> > sponges, hemostatic agents made from bovine collagen and oxidized
> > cellulose are used for stopping bleeding. Additionally products
> > containing thrombin and/or fibrinogen are used to assist the body's
> > natural clotting mechanism to achieve hemostasis.

# Marketing History

> > BioGlue was approved in the United States for use in the repair of
> > acute thoracic aortic dissection under the HDE regulations (H990007)
> > in December 1999 and has been marketed in the U.S. since that time.
>
> > Commercial distribution of the device outside of the U.S. started in
> > April 1998. Currently the device is marketed in the following
> > countries: Argentina, Australia, Austria, Belgium, Bolivia, Brazil,
> > Bulgaria, Canada, China, Czech Republic, Denmark, Egypt, Finland,
> > France, Germany, Greece, Hungary, India, Iceland, Ireland, Israel,
> > Italy, Lebanon, Liechtenstein, The Netherlands, New Zealand, Norway,
> > Portugal, South Africa, Spain, Sweden, Switzerland, Syria, Turkey,
> > United Arab Emirates, United Kingdom, and Venezuela.
>
> > BioGlue Surgical Adhesive has not been withdrawn from marketing for
> > any reason relating to safety or effectiveness of the device.

# Potential Adverse Effects of the Device on Health

> > The following adverse events could potentially occur due to the
> > composition of the device, the mode of application, or the disease
> > process:

-   Failure of product to adhere to tissue

-   Application of adhesive to tissue not targeted for procedure

-   Inflammatory, immune, or local and systemic allergic reaction

-   Mineralization of tissue

-   Local tissue necrosis

-   Thrombosis and thromboembolism

-   Possible transmission of infectious agents from material of animal
    > origin

> > Reference Table 12 for procedure related complications observed
> > within the U.S. IDE cardiac and vascular repair clinical trial.

# Summary of Preclinical Studies

## Laboratory Studies

### Biocompatibility

> > CryoLife conducted biocompatibility testing of the cured BioGlue
> > implant material and all delivery system materials contacting the
> > patient or adhesive solutions in accordance with GLPs (Good
> > Laboratory Practices). All of the irradiated materials that come in
> > contact with the BioGlue adhesive solutions during storage were also
> > assessed for extractables. The following table summarizes testing
> > done on the cured BioGlue implant:
>
> > Table 1. Biocompatibility Testing Results -- Cured BioGlue Implant

+---------------+--------------+-----------------+---------------------+
| **Test        | **           | **Test and      | *                   |
| Performed**   | Extract(s)** | Control(s)**    | *Results/Comments** |
+---------------+--------------+-----------------+---------------------+
| Cytotoxicity  | MEM          | Natural rubber  | L-929 cells gave a  |
| (ISO)         |              | (+)             | grade 2 (mild)      |
|               |              |                 | reactivity score    |
|               |              | Silicone tubing | with test extract   |
|               |              | (-)             | at 48 hours         |
+---------------+--------------+-----------------+---------------------+
| Sensitization | Saline and   | Saline and CSO  | No sensitization    |
| (             | CSO          | (-)             | was observed        |
| Maximization) |              |                 |                     |
|               |              | DNCB (+) with   |                     |
|               |              | and without     |                     |
|               |              | activation      |                     |
+---------------+--------------+-----------------+---------------------+
| I             | Saline and   | Saline and CSO  | No toxicity         |
| ntracutaneous | CSO          |                 | observed in either  |
| Toxicity      |              |                 | extract             |
| (ISO/USP)     |              |                 |                     |
+---------------+--------------+-----------------+---------------------+
| Systemic      | Saline (IV)  | Saline and CSO  | No signs of         |
| Toxicity      | and CSO (IP) |                 | toxicity            |
| (ISO/USP)     |              |                 |                     |
+---------------+--------------+-----------------+---------------------+
| Hemolysis     | Saline       | Saline (-)      | 4.45% hemolysis,    |
| (DHEW)        |              |                 | considered to be    |
|               |              | Water (+)       | non-hemolytic       |
+---------------+--------------+-----------------+---------------------+
| Rabbit        | Saline       | Saline (-)      | \<0.5 °C rise in    |
| pyrogen (ISO) |              |                 | all                 |
|               |              |                 | ra                  |
|               |              |                 | bbits-non-pyrogenic |
+---------------+--------------+-----------------+---------------------+

> > Biocompatibility tests conducted on the applicator tip and solutions
> > cartridge components include cytotoxicity, systemic and
> > intracutaneous toxicity, sensitization, and pyrogenicity. All test
> > results are "pass" or are "non-toxic". There was also data in the
> > file regarding the applicator tip connector extenders and extender
> > tubing. These passed the cytotoxicity, sensitization,
> > irritation/intracutaneous toxicity, and systemic toxicity tests.
>
> > CryoLife also evaluated BioGlue implant tissue response as part of a
> > three month implant study to determine the effects of BioGlue in the
> > surgical repair of aortic dissection in sheep (see section 8.2
> > Animal Studies). The observations of inflammation, necrosis,
> > calcification and fibrosis in the BioGlue treated group were found
> > to be consistent with a normal foreign body reaction.
>
> > [Conclusions from the biocompatibility testing:]{.underline}
>
> Based on these test results, the device is biocompatible for its
> intended use.

### Analytical and Functional Testing

> > Analytical and functional testing is conducted on each lot of
> > BioGlue® Surgical Adhesive to ensure that it meets established
> > product specifications designed to ensure the device is safe for its
> > intended use. Analytical Tests include: UV-Vis Spectrophotometric
> > Profile of Bovine Serum Albumin, pH Determination of Bovine Serum
> > Albumin Solutions, Monomeric Content of Bovine Serum Albumin by
> > SDS-PAGE, Protein Concentration of Bovine Serum Albumin Solutions by
> > Colorimetric Assay, Glutaraldehyde Concentration Determination by
> > Hydroxylamine-HCl Titration, and Extent of Autopolymerization of
> > Glutaraldehyde by Absorbance Ratio. Functional tests include
> > Adhesive Cure Rate and Adhesive Shear.
>
> > [Conclusions from functional testing:]{.underline}
>
> > The device possesses adequate bonding strength and is reproducible
> > in its chemical characteristics.

## Animal studies

### Surgical Repair of Aortic Dissections in Sheep

> > A three-month study to determine the effects of BioGlue in the
> > surgical repair of aortic dissection in sheep was conducted to
> > evaluate device performance. This study involved use of a prototype
> > device, the BG2000, which utilized aseptically transferred solutions
> > that had been sterilized by filtration and aseptically filled into
> > the cartridges at the time of surgery. The current BG3000 device
> > uses pre-filled cartridges that have been gamma irradiated.
> > Additional animal studies employing the BG3000 were not conducted
> > because the results of *in vitro* testing of the BG3000 demonstrated
> > that the adhesive (shear strength) and monomeric impurity properties
> > were not altered by the gamma irradiation.
>
> > A previously reported model of descending aortic dissection[^1] was
> > created in 30 sheep. After the aortic dissection was created, the
> > surgeon determined if the dissection met the acceptance criteria
> > established in the study protocol (i.e., a false lumen volume \<50%
> > of the total aortic volume, length of \<7.1 cm and width \< 2.6 cm).
> > Dissections that did not meet these criteria were considered
> > unstable for repair. Animals with acceptable dissections were then
> > randomized in a blinded fashion to surgical repair of the proximal
> > flap alone, or repair by gluing the layers of the dissection
> > together with BioGlue and surgical repair of the proximal flap.
> > There were 26 aortic dissections that met the acceptance criteria,
> > with 13 animals randomized to surgical repair alone and 13 to
> > BioGlue repair. The dissections varied in size from 5.0 to 7.0 cm
> > long (average 5.2), 1.2 to 2.5 cm wide (average 1.4), encompassing
> > 20-50% (average 35%) of the aortic volume. There were no statistical
> > variations between the dimensions of the dissection in the surgical
> > and BioGlue groups.
>
> > In the BioGlue group, four animals died of causes unrelated to the
> > BioGlue (3 pneumonia/weather stress, 1 tension pneumothorax
> > immediately following surgery). In all four of these animals, the
> > aortic dissection was completely obliterated or healed. In the 9
> > remaining BioGlue animals, one animal died of chronic aortic
> > aneurysm rupture at 51 days (due to mycotic super-infection of a
> > technical glue failure) and in 8 animals surviving \> 90 days the
> > aortic dissection was completely healed (i.e. all of the layers of
> > the aorta were fused and no false lumen or blind pouch observed)
> > without signs of proximal or distal progression.
>
> > In the surgical control group, 1 animal died of pneumonia/weather
> > stress. Four animals died within 24 hours of proximal or distal
> > aneurysm progression and rupture. Eight animals survived 90 days. In
> > 2 of the 8, the dissection healed after 3-3.5 cm of progression. In
> > 2 of the 8, a chronic dissection formed at the surgical repair
> > distal suture line and in 4 of the 8, a chronic dissection formed at
> > re-entry points unrelated to the surgical repair site. In the
> > chronic dissections, the false lumen made up 25-75% of the total
> > aortic lumen. In all of the chronic dissections, the wall of the
> > aorta was thinning and the diameter of the aorta was expanding,
> > suggesting early aortic aneurysm formation.
>
> > Tissue response evaluations were also conducted.
>
> > [Conclusions from the animal studies:]{.underline}
>
> > Based on the results of this study, repair of aortic dissection
> > using BioGlue^®^ as an adjuvant to surgery in the sheep model was
> > superior to surgery alone because:

-   BioGlue decreased the incidence of acute post-repair rupture of the
    > aorta from 30% to 0%.

-   BioGlue decreased the incidence of re-dissection at the site of
    > distal surgical repair from 17% to 0% in animals surviving 90
    > days.

-   BioGlue decreased the incidence of dissection progression prior to
    > healing from 17% to 0% in animals surviving 90 days.

-   BioGlue decreased chronic dissection formation from 75% to 0% in
    > animals surviving 90 days.

### Thoracic Aorta Repair with BioGlue in Coagulopathic Sheep

> **Summary**
>
> The objective of this study was to investigate the efficacy of BioGlue
> for thoracic aortic surgical repair. The coagulopathic sheep model,
> which was developed for this study, simulates needle hole and surgical
> bleeding from the anastomoses of synthetic graft to the thoracic aorta
> in coagulopathic surgical patients. The study hypothesized that
> induction of coagulopathy in sheep would model clinical needle hole
> and surgical bleeding from synthetic graft anastomoses and that the
> tissue bioadhesive would control post-operative blood loss.
>
> A secondary objective of the study was to evaluate the histopathology
> of the treated area over twenty-four months.
>
> **Methods**
>
> Sheep were given 600 mg aspirin suppositories for two days prior to
> surgery, and two IV boluses of heparin (400 units/kg) during surgery.
> A bypass conduit was created by two end-to-side anastomoses of
> synthetic graft to the partially occluded thoracic aorta. The bypassed
> native aorta was then occluded. Experimentals (n=9) were treated with
> BioGlue and controls (n=5) were treated with Surgicel^®^ to effect
> hemostasis intra-operatively. Post-operative bleeding was measured by
> chest tube output. Statistics were analyzed by the student T-test on
> normal or log transformed data or the rank-sum test.
>
> **Results**
>
> Post-surgical bleeding was significantly and dramatically controlled
> in the experimental group compared to controls as determined by total
> chest tube output (CON median = 955 ml vs. EXP median = 470 ml,
> p\<0.003). Intra-operative blood loss was also reduced in the
> experimental group compared to the control group (CON = 422 ml vs. EXP
> = 241 ml) but, this was not significant (p=0.3). The average hourly
> rate of blood loss in the BioGlue group showed a significant reduction
> over both the first two hours (EXP = 92.5 cc/hr, CON = 210 cc/hr,
> p=0.005) and the duration of recovery (EXP = 85.5 cc/h vs. CON = 158.3
> cc/h, p=0.046). Additionally, total blood loss (post-operative and
> intra-operative) was significantly reduced in the experimental group
> (p\<0.008).
>
> No inflammatory response to BioGlue was noted within 3 months
> post-operative. There was no fibrotic response and no foreign body
> granulomatous response. No giant cells were present in any of the
> samples. Following long-term (\>two years) survival, histopathology
> revealed bland appearing areas of BioGlue, which were interpreted to
> be areas of degradation and resorption. These areas were relatively
> acellular, and the mechanisms of the degradation remain unknown.
> Potentially, some of the adjacent collagen strands may represent
> remodeled BioGlue in these specimens.
>
> During the follow-up period one of the BioGlue treated animals gave
> birth to a healthy lamb.
>
> **Conclusions**
>
> The end-to-side anastomosis of synthetic graft to the thoracic aorta
> in sheep treated with heparin and aspirin provides a clinically
> relevant coagulopathic model. BioGlue^®^ demonstrated significant
> intra- and post-operative hemostasis in a coagulopathic sheep model
> when compared to the control treatment (Surgicel^®^). The host's
> reaction to the BioGlue was minimal. Following long-term (\>two years)
> survival, histopathology revealed bland appearing areas of BioGlue,
> which were interpreted to be areas of degradation and resorption of
> BioGlue. This tissue bioadhesive should prove extremely beneficial,
> clinically, for coagulopathic patients needing thoracic aortic or
> vascular surgery.

### Biodegradation

> Once BioGlue is fully polymerized, it is an insoluble material.
> Polymerized BioGlue remained intact *in vitro* when kept in water over
> 30 days. Additionally, the histopathology of early (30 days) time
> points does not indicate dissolution of the implant.
>
> When studied in various species (including human) and in varied
> implant sites, no implant degradation was observed for up to 12 months
> (Gundry *et al.*, 2000). The sole observation of biodegradation was in
> a long-term (24-month) vascular BioGlue implant in the sheep (See
> section 8.2.2). In previously reported animal explants a chronic
> inflammatory response was observed, with giant cells and granulomatous
> inflammation, typical of a foreign body response. In humans, the
> paucity of a chronic inflammatory response up to 9 months was noted
> (Hewitt *et al.*, 2000and the animal study discussed in section
> 8.2.2). In the animal study discussed in 8.2.2, the hosts' (sheep)
> reaction to BioGlue at 3 months was strikingly lacking an inflammatory
> response. A foreign body response was observed at 83 days, though
> minimal and inconsistent.
>
> The 24-month sheep explant showed a range of phases of the remodeling
> of the BioGlue implant. Some regions exhibited no degradation (regions
> of encapsulation), while others showed signs of incipient degradation
> (representing a phase in the putative process whereby BioGlue was
> remodeled via a normal healing response). Basically, cells infiltrate
> BioGlue as the degradation and resorption process evolves. Prior to
> resorption, BioGlue has frequently been reported to become
> encapsulated with tissue in a normal foreign body healing response or
> to elicit a minimal inflammatory response. The lack of histopathologic
> response in humans suggests that the implant may remain for a longer
> period than that observed in animals.
>
> BioGlue is a protein cross-linked at its lysine side chains with
> glutaraldehyde. The remainder of the BSA molecule is open to attack by
> proteinases. The sensitivity of glutaraldehyde cross-linked proteins
> and tissues to proteinases has been well studied in bioprosthetic
> grafts. These cross-linked tissues remain sensitive to natural
> proteolysis, albeit at a substantially slower rate.

# Summary of Clinical Studies

> > In June 1998, CryoLife, Inc. began a clinical trial investigating
> > the use of BioGlue as an adjunct in the surgical repair of acute,
> > Stanford Type A aortic dissections. CryoLife filed a Humanitarian
> > Device Exemption (HDE) for the use of BioGlue in the surgical repair
> > of acute thoracic aortic dissections, which was approved by FDA in
> > December 1999 (H990007). The data is suggestive of a benefit in
> > terms of 1) decreased rate of reoperation for bleeding and other
> > bleeding complications without the need for other hemostatic devices
> > and/or pharmacological agents, 2) fewer intraoperative blood
> > transfusions, and 3) reinforcement of friable tissue of the
> > dissected aorta without the need for pledgets. CryoLife gained
> > approval in May 2000 to investigate the use of BioGlue for sealing
> > anastomotic sites in cardiac and vascular repairs. Following is
> > information from the cardiac and vascular repair investigation:

## Study Design

> > The "BioGlue Surgical Adhesive Effectiveness and Safety Trial as a
> > Surgical Adjunct in Cardiac and Vascular Surgical Repairs ("BEST"
> > Trial) was a prospective, multi-center, randomized controlled trial.
> > Randomized cardiac and vascular repairs include an adjunctive
> > BioGlue prophylactic treatment and a control group (standard
> > surgical repair). The overall objective was to collect clinical data
> > concerning the safety and effectiveness of BioGlue used as an
> > anastomotic sealant to provide hemostasis.
>
> > Cardiac and vascular repair procedures included but were not limited
> > to the surgical repair/reconstruction of the following clinical
> > conditions: ventricular aneurysm/rupture; aortic aneurysm/dilatation
> > (root, ascending arch, descending thoracic, thoracoabdominal,
> > abdominal, and aortoiliac); traumatic aortic transection;
> > annulo-aortic ectasia; and vascular bypass or repair.
>
> > Patients were randomized to receive standard surgical repair with
> > BioGlue applied to the anastomotic site (BioGlue group) or standard
> > surgical anastomotic repair alone (control group).

## Patient Assessment

> > [Effectiveness Evaluations]{.underline}
>
> > The BioGlue group and the standard surgical repair group were
> > compared to determine BioGlue's effectiveness for the following
> > endpoints:
>
> > **Primary Evaluation**
>
> > Anastomotic hemostasis (yes or no) of each of the repaired
> > anastomotic sites. Anastomotic hemostasis was defined as an
> > anastomosis that does not require additional agents (pledgets,
> > sutures, hemostatic devices, antifibrinolytic agents, thrombin
> > glues, fibrin glues) at the treated site(s) to control bleeding at
> > any point during the course of the original operation. Results were
> > also evaluated on a "per patient" basis. Patients with anastomotic
> > hemostasis at all anastomotic sites were considered successful.
>
> > **Secondary Evaluations**

-   Quantity, type, and number of donor exposures of blood replacement
    > products administered.

-   Type of additional agents used (pledgets, sutures, hemostatic
    > devices, antifibrinolytic agents, thrombin glues, fibrin glues)

-   Re-operation due to anastomotic site bleeding.

-   Major complications/adverse events through final follow-up.

-   Minor complications/adverse events through final follow-up.

-   Early hospital discharge mortality and mortality through last
    > follow-up.

> > **Cost Benefit Evaluations**

-   Total cardiopulmonary bypass time (when applicable).

-   Time required for aortic cross-clamp (when applicable).

-   Total operative time (skin incision to skin closure).

-   Total time in Intensive Care Unit.

-   Total hospitalization time.

> > **Safety Evaluations**
>
> > The criteria for evaluating safety in this patient population were:

-   Unanticipated Adverse Device Effects (UADE).

-   Device complications.

-   Surgical procedure complications.

## Demographic Data

> > A total of 151 patients were treated at 6 investigational sites in
> > the cardiac and vascular repair arm of the U.S. IDE clinical trial.
> > Pertinent information about the patient population is presented in
> > Tables 2 and 3. Surgical procedures performed are shown in Table 4.
>
> Table 2 -- Summary of Subjects

  ----------------- ----------------- ----------------- -----------------
                    **Treatment                         
                    Group**                             

  **Population**    **Surgical Repair **Conventional    **Total**
                    with BioGlue**    Surgical Repair** 

  All Randomized    76                75                151

  Cross Over        N/A               1                 1

  Intent-to-Treat   76                74                150

  Evaluable         76                74                149

  Safety            77                74                151
  ----------------- ----------------- ----------------- -----------------

> *Table 3 -- Demographic Characteristics (*All randomized patients)

  -------------------- -------------- ---------------- --------------- --------------
                       **Treatment                                     
                       Group**                                         

  **Characteristic**   **Surgical     **Conventional   **Crossover**   **Total**
                       Repair with    Surgical                         
                       BioGlue**      Repair**                         

  Age (years)                                                          

  N                    76             74               1               151

  Mean (SD)            63.4 (17.2)    66.3 (12.7)      73.8 (N/A)      64.8 (15.1)

  Min, Max             21, 87         25, 86           N/A             20, 87

                                                                       

  Gender                                                               

  Male                 49             48               0               97

  Female               27             26               1               54

  Total                76             74               1               151

  Race                                                                 

  African-American     6              6                0               12

  Asian                1              1                0               2

  Caucasian            67             66               1               133

  Hispanic             2              1                0               3

  Total                76             74               1               151
  -------------------- -------------- ---------------- --------------- --------------

> Table 4 -- Cardiac and Vascular Procedures Included

  -------------------- ------------- ---------------- --------------- ------------
                       **Treatment                                    
                       Group**                                        

  **System**           **Surgical    **Conventional   **Crossover**   **Total**
                       Repair with   Surgical                         
                       BioGlue**     Repair**                         

  Cardiac              24            25               0               49
  Procedures^\*\*^                                                    

  Aortic Procedures^†^ 57            47               1               105

  Peripheral Vascular  25            23               0               48
  Procedures^\*\*\*^                                                  

  Total                106           95               1               202
  -------------------- ------------- ---------------- --------------- ------------

> \*\**Cardiac repairs include: aortic root replacements (4),
> aortoplasty (1), aortic valve annuloplasty (5), aortic valve
> resuspension (1), aortic valve replacement (23), Bentall procedure
> (2), composite valved conduit procedures (8), mitral valve
> replacements (2), Ross procedure (2), coronary artery bypass grafting
> (1).*
>
> ^†^*Aortic aneurysm repairs include: abdominal aortic aneurysm (21),
> ascending aortic aneurysm (21), ascending/ transverse aortic arch
> aneurysm (9), ascending/ transverse arch/ descending aortic aneurysm
> (1), descending aortic aneurysm (8), thoracoabdominal aortic aneurysm
> (32), transverse aortic arch aneurysm (12), Type B aortic dissection
> (1)*
>
> *\*\*\*Peripheral vascular repairs include: aorto-femoral bypass (5),
> aorto-iliac bypass (2), aorto-innominate bypass (1), carotid bypass
> (1), carotid endarterectomy (19), femoral-distal bypass (3),
> femoral-femoral bypass (2), femoral-popliteal bypass (5),
> hepatic-renal bypass (1), popliteal-dorsalis pedis bypass (1),
> profunda endarterectomy (1), renal bypass (6), renal endarterectomy
> (1)*

## Data Analysis and Results

> > The tables and figures in this section present information from the
> > cardiac and vascular repair arm of the U.S. IDE clinical trial.
>
> > [Efficacy Data]{.underline}
>
> > Table 5 presents the intra-operative hemostasis data for the
> > intent-to-treat patients on both a "per patient" and a "per
> > anastomotic repair site" basis. The proportion of both patients and
> > anastomotic repair sites achieving hemostasis based upon the
> > protocol definition was statistically greater in the BioGlue group
> > (Fisher's Exact Test, p \< 0.05).
>
> Table 5 -- Intra-operative Hemostasis -- Intent-to-Treat Patients
> (Success/Total)

  --------------------- ---------------- ---------------- ----------------
                        Treatment Group                   

                        Surgical Repair  Conventional     P value
                        With BioGlue     Surgical Repair  

  Per patient^\*^       61% (46/76)      39% (29/74)      0.014

  Per Repair Site^\*\*^ 81% (164/202)    57% (105/184)    \<0.001
  --------------------- ---------------- ---------------- ----------------

> ^\*^ *Hemostasis on a "per patient" basis was defined as hemostasis of
> 100% of the anastomotic repair sites.*
>
> *^\*\*^ The average number of repair sites (anastomoses) per patient
> were 2.6 (range: 1 to 8).*
>
> > Use of intra-operative blood products is outlined in Table 6. No
> > statistically significant differences were noted between the BioGlue
> > group and the control group based upon a one-sided 95% confidence
> > interval of the difference between the treatment means.
>
> *Table 6 --Intra-operative Blood Products and Donor Exposures*
> (Intent-to-Treat Patients)

  --------------------------- --------------------- ---------------------
                              Treatment Group       

                              Surgical Repair With  Conventional Surgical
                              BioGlue               Repair

  Red Blood Cells                                   

  N                           76                    74

  Mean (SD)                   2.3 (3.6)             1.9 (2.4)

  Min, Max                    0, 22                 0, 12

                                                    

  Platelets                                         

  N                           76                    74

  Mean (SD)                   5.1 (10.1)            5.2 (10.0)

  Min, Max                    0, 60                 0, 50

                                                    

  Fresh Frozen Plasma                               

  N                           75                    73

  Mean (SD)                   3.8 (6.6)             3.3 (5.0)

  Min, Max                    0, 30                 0, 19

                                                    

  Cryoprecipitate                                   

  N                           74                    72

  Mean (SD)                   4.3 (11.9)            2.0 (8.3)

  Min, Max                    0, 60                 0, 40

                                                    

  Total Number of Donor                             
  Exposures                                         

  N                           48                    51

  Mean (SD)                   20.6 (26.3)           14.2 (18.2)

  Min, Max                    0, 106                0, 89
  --------------------------- --------------------- ---------------------

> > Investigators in this trial documented their usage of pledgeted
> > sutures to reinforce their primary repair. Anastomotic sites treated
> > with BioGlue had a statistically lower incidence of pledget usage on
> > the primary repair when compared to the control group (Table 7).
>
> Table 7 -- Pledgets on Primary Repair - Intent-to-Treat Anastomotic
> Sites (Success/Total Number of Anastomotic Sites)

+----------------------------+--------------+-------------+-----------+
|                            | Treatment    |             |           |
|                            | Group        |             |           |
+----------------------------+--------------+-------------+-----------+
|                            | Surgical     | C           | P Value   |
|                            | Repair with  | onventional |           |
|                            | BioGlue      | Surgical    |           |
|                            |              | Repair      |           |
+----------------------------+--------------+-------------+-----------+
| Pledgets Used on Primary   | 26%          | 36%         | 0.047     |
| Repair                     |              |             |           |
|                            | (53/202)     | (66/184)    |           |
+----------------------------+--------------+-------------+-----------+

> > Any anastomotic repair site that was not immediately hemostatic was
> > evaluated to determine the additional methods used to obtain
> > hemostasis. There was no statistical difference noted in the
> > additional measures taken to obtain hemostasis, which indicates that
> > BioGlue did not inhibit the surgeons ability to obtain hemostasis
> > through use of conventional measures or additional BioGlue. These
> > results are summarized in Table 8 below:
>
> *Table 8 -- Measures Required to Obtain Hemostasis - Intent-to-Treat
> Bleeding Anastomotic Sites (Bleeding Anastomotic Sites Requiring
> Measure/Total Bleeding Sites)*

  ----------------------- ---------------- ---------------- -------------
                          Treatment Group                   

                          Surgical Repair  Conventional     P value
                          With BioGlue     Surgical Repair  

  Make-up Stitches        82% (31/38)      81% (64/79)      1.00

  Hemostatic Device^\*^   8% (3/38)        10% (8/79)       1.00

  Additional BioGlue      55% (21/38)      N/A              N/A

  Other^†^                8% (3/38)        19% (15/79)      0.17
  ----------------------- ---------------- ---------------- -------------

> > ^\*^ *Hemostatic Devices included Surgicel^®^, Avitene^®^,
> > Gelfoam^®^, Fibrin Glue, Thrombin Glue.*
>
> > ^†^ *Other includes: Additional pledgets (16), FloSeal (1), Teflon
> > felt ring (1)*
>
> > The study protocol allowed investigators to "cross-over" and use
> > BioGlue for control patients who suffered uncontrollable bleeding.
> > Only one patient was noted to have uncontrollable bleeding. The
> > investigator was able to obtain hemostasis at all anastomotic sites
> > after using BioGlue for this patient.
>
> > Incidence of re-operation for anastomotic site bleeding is presented
> > in Table 9. Only one patient had a re-operation due to anastomotic
> > site bleeding.
>
> Table 9 -- Re-operation Due to Anastomotic Site Bleeding

+-----------------------+----------------+----------------+------------+
|                       | Treatment      |                |            |
|                       | Group          |                |            |
+-----------------------+----------------+----------------+------------+
|                       | Surgical       | Conventional   | One-Sided  |
|                       | Repair With    | Surgical       | 95%        |
|                       | BioGlue        | Repair         | Confidence |
|                       |                |                | Interval   |
|                       | N (%)          | N (%)          |            |
+-----------------------+----------------+----------------+------------+
| Re-operation          | 0 (0.0%)       | 1 (1.4%)       | \[\--,     |
|                       |                |                | 0.9\]      |
+-----------------------+----------------+----------------+------------+

> > Table 10 shows a summary of intra-operative times, days spent in the
> > ICU, and total hospitalization time. The differences between the
> > BioGlue group and the control group were not statistically
> > significant.
>
> *Table 10 -- Procedure, ICU, and Hospitalization Times*
> (Intent-to-Treat)

+-------------------------------+------------------+------------------+
|                               | Treatment Group  |                  |
+-------------------------------+------------------+------------------+
|                               | Surgical Repair  | Conventional     |
|                               | With BioGlue     | Surgical Repair  |
+-------------------------------+------------------+------------------+
| **Procedure Times**           |                  |                  |
+-------------------------------+------------------+------------------+
| Cardiopulmonary Bypass Time\* |                  |                  |
|                               |                  |                  |
| (minutes)                     |                  |                  |
+-------------------------------+------------------+------------------+
| N                             | 34               | 35               |
+-------------------------------+------------------+------------------+
| Mean (SD)                     | 168.1 (67.4)     | 144.2 (60.6)     |
+-------------------------------+------------------+------------------+
| Min, Max                      | 54, 358          | 54, 387          |
+-------------------------------+------------------+------------------+
|                               |                  |                  |
+-------------------------------+------------------+------------------+
| Cross-Clamp Time\* (minutes)  |                  |                  |
+-------------------------------+------------------+------------------+
| N                             | 54               | 55               |
+-------------------------------+------------------+------------------+
| Mean (SD)                     | 74.0 (46.1)      | 69.1 (41.3)      |
+-------------------------------+------------------+------------------+
| Min, Max                      | 10, 196          | 19, 196          |
+-------------------------------+------------------+------------------+
|                               |                  |                  |
+-------------------------------+------------------+------------------+
| Total Operative Time          |                  |                  |
| (minutes)                     |                  |                  |
+-------------------------------+------------------+------------------+
| N                             | 75               | 73               |
+-------------------------------+------------------+------------------+
| Mean (SD)                     | 237.7 (125.1)    | 228.7 (100.8)    |
+-------------------------------+------------------+------------------+
| Min, Max                      | 85, 650          | 60, 515          |
+-------------------------------+------------------+------------------+
|                               |                  |                  |
+-------------------------------+------------------+------------------+
| **ICU Time**                  |                  |                  |
+-------------------------------+------------------+------------------+
| Days in ICU\*                 |                  |                  |
+-------------------------------+------------------+------------------+
| N                             | 70               | 72               |
+-------------------------------+------------------+------------------+
| Mean (SD)                     | 3.9 (5.6)        | 4.8 (7.1)        |
+-------------------------------+------------------+------------------+
| Min, Max                      | 0, 32            | 0, 36            |
+-------------------------------+------------------+------------------+
|                               |                  |                  |
+-------------------------------+------------------+------------------+
| **Hospitalization Time**      |                  |                  |
+-------------------------------+------------------+------------------+
| Days in Hospital              |                  |                  |
+-------------------------------+------------------+------------------+
| N                             | 72               | 73               |
+-------------------------------+------------------+------------------+
| Mean (SD)                     | 9.5 (10.6)       | 10.9 (9.7)       |
+-------------------------------+------------------+------------------+
| Min, Max                      | 1, 81            | 1, 55            |
+-------------------------------+------------------+------------------+

> > *\* Where applicable.*
>
> > [Safety Data]{.underline}
>
> > Mortality rates for intent-to-treat in this trial are presented in
> > Table 11. No differences were observed in either early (through
> > hospital discharge) mortality or late (through final follow-up)
> > mortality.
>
> *Table 11 -- Mortality Rates -- Intent-to-Treat Patients
> (Event/Total)*

  ----------------------- ---------------- ---------------- -------------
                          Treatment Group                   

                          Surgical Repair  Conventional     One-Sided 95%
                          With BioGlue     Surgical Repair  Confidence
                                                            Interval

  Early/Hospital          3.9% (3/76)      2.7% (2/74)      \[\--, 6.1\]
  Discharge (\<30 days)                                     

  Post-operative          1.3% (1/76)      4.1% (3/74)      \[\--, 3.9\]
  Follow-up (3 months)                                      
  ----------------------- ---------------- ---------------- -------------

> > Table 12 shows a complete listing of all procedure related
> > complications reported for the patients in this trial. There were no
> > statistically significant differences in complication rates between
> > the BioGlue group and the control group. There were two
> > complications that were device-related. One adverse event occurred
> > from application of BioGlue to non-target tissue and the other
> > adverse event occurred when BioGlue was applied to a wet field. Both
> > complications are included in the Instructions for Use as a warning
> > and a precaution, respectively.
>
> **Table 12 - Observed Adverse Events**

+-----------------------+---+------+-----+---+------+-----+---------+
| Adverse Event         | B |      |     | C |      |     | P-Value |
| Description           | i |      |     | o |      |     |         |
|                       | o |      |     | n |      |     |         |
|                       | G |      |     | t |      |     |         |
|                       | l |      |     | r |      |     |         |
|                       | u |      |     | o |      |     |         |
|                       | e |      |     | l |      |     |         |
|                       | G |      |     | G |      |     |         |
|                       | r |      |     | r |      |     |         |
|                       | o |      |     | o |      |     |         |
|                       | u |      |     | u |      |     |         |
|                       | p |      |     | p |      |     |         |
|                       |   |      |     |   |      |     |         |
|                       | N |      |     | N |      |     |         |
|                       | = |      |     | = |      |     |         |
|                       | 7 |      |     | 7 |      |     |         |
|                       | 7 |      |     | 4 |      |     |         |
|                       |   |      |     |   |      |     |         |
|                       | n |      |     | n |      |     |         |
|                       | % |      |     | % |      |     |         |
|                       | # |      |     | # |      |     |         |
|                       | e |      |     | e |      |     |         |
|                       | v |      |     | v |      |     |         |
|                       | e |      |     | e |      |     |         |
|                       | n |      |     | n |      |     |         |
|                       | t |      |     | t |      |     |         |
|                       | s |      |     | s |      |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Application of        | 1 | 1.3% | 1   | 0 | 0%   | 0   | 1.000   |
| Adhesive to           |   |      |     |   |      |     |         |
| Non-Targeted          |   |      |     |   |      |     |         |
| Tissue^1^             |   |      |     |   |      |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Death                 | 5 | 6.5% | 5   | 5 | 6.8% | 5   | 0.999   |
+-----------------------+---+------+-----+---+------+-----+---------+
| Failure of Products   | 1 | 1.3% | 1   | 0 | 0%   | 0   | 1.000   |
| to Adhere to          |   |      |     |   |      |     |         |
| Tissue^1^             |   |      |     |   |      |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Hemorrhage            | 3 | 3.9% | 3   | 3 | 4.1% | 3   | 1.000   |
+-----------------------+---+------+-----+---+------+-----+---------+
| Infection             | 1 | 1    | 15  | 1 | 1    | 13  | 0.653   |
|                       | 3 | 6.9% |     | 0 | 3.5% |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Inflammatory, Immune  | 2 | 2.6% | 2   | 0 | 0%   | 0   | 0.497   |
| Systemic Allergic     |   |      |     |   |      |     |         |
| Reaction^2^           |   |      |     |   |      |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Irreversible          | 0 | 0%   | 0   | 1 | 1.4% | 1   | 0.490   |
| Morbidity             |   |      |     |   |      |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Ischemia              | 3 | 3.9% | 3   | 2 | 2.7% | 2   | 1.000   |
+-----------------------+---+------+-----+---+------+-----+---------+
| Myocardial Infarction | 3 | 3.9% | 3   | 1 | 1.4% | 1   | 0.620   |
+-----------------------+---+------+-----+---+------+-----+---------+
| Neurological Deficits | 5 | 6.5% | 6   | 1 | 2    | 18  | 0.009   |
|                       |   |      |     | 6 | 1.6% |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Organ System          | 3 | 3.9% | 4   | 2 | 2.7% | 2   | 1.000   |
| Dysfunction/Failure   |   |      |     |   |      |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Paraplegia            | 1 | 1.3% | 3   | 2 | 2.7% | 3   | 0.615   |
+-----------------------+---+------+-----+---+------+-----+---------+
| Pleural Effusion      | 2 | 2    | 25  | 2 | 2    | 22  | 0.855   |
|                       | 0 | 6.0% |     | 1 | 8.4% |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Renal                 | 1 | 1    | 13  | 9 | 1    | 10  | 0.492   |
| Dysfunction/Failure   | 3 | 6.9% |     |   | 2.2% |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Respiratory           | 1 | 1    | 18  | 1 | 1    | 15  | 1.000   |
| Dysfunction/Failure   | 3 | 6.9% |     | 2 | 6.2% |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Stroke or Cerebral    | 1 | 1.3% | 1   | 3 | 4.1% | 5   | 0.360   |
| Infarction            |   |      |     |   |      |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Thromboembolism       | 1 | 1.3% | 1   | 1 | 1.4% | 4   | 1.000   |
+-----------------------+---+------+-----+---+------+-----+---------+
| Thrombosis            | 0 | 0%   | 0   | 1 | 1.4% | 1   | 0.490   |
+-----------------------+---+------+-----+---+------+-----+---------+
| Other^3,4^            | 4 | 5    | 108 | 4 | 5    | 100 | 0.514   |
|                       | 6 | 9.7% |     | 0 | 4.1% |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+

> ^1^ These adverse events were device related. Both complications were
> clearly warned against in the IFU.
>
> ^2^ These adverse events were not device related. One patient had an
> allergic reaction to a preoperative antibiotic and the other patient
> had an allergic reaction to Protamine.
>
> ^3^ Other adverse events observed in the BioGlue treated clinical
> trial patients were as follows: Acidosis (1%), Acute shortness of
> breath (1%), Altered mental status (3%), Anemia (5%), Atelectasis
> (8%), Cardiac arrhythmia (22%), Cerebral hemorrhage (1%), Colecystitis
> (1%), Coagulopathy (1%), Congestive Heart Failure (4%), Decreased
> femoral pulse (1%), Deep Vein Thrombosis (1%), Depression (4%),
> Diarrhea (3%), Dysphagia (5%), Edema (3%), Fever (3%), Heart
> enlargement (4%), Hematuria (1%), Hemoptysis (1%), Hernia (4%),
> Hoarseness (1%), Hypotension (1%), Ileus (4%), Incisional pain (3%),
> Lymphatic fistula (1%), Malnutrition (5%), Nausea (3%), Perforated
> viscus (1%), Pericardial effusion (1%), Pneumothorax (3%), Rectal
> bleeding (1%), Seizure (1%), Thigh and back pain (3%),
> Thrombocytopenia (1%), Urinary retention (4%), Vocal cord paralysis
> (3%).
>
> 4 Other adverse events observed in the Control Group clinical trial
> patients were as follows: Abdominal pain (1%), Abnormal lab value
> (5%), Acidosis (1%), Altered mental status (3%), Anemia (3%), Angina
> (1%), Aphasia (1%), Atelectasis (4%), Back pain (1%), Cardiac
> arrhythmia (19%), Cerebral hemorrhage (3%), Congestive heart failure
> (1%), Diarrhea (3%), Dizziness (1%), Duodenal ulcer (1%), Dysphagia
> (1%), Edema (1%), Emphysema (1%), Encephalopathy (1%), Failed
> extubation (1%), Fever (3%), Heart block (2%), Hematuria (1%),
> Hemothorax (1%), Hernia (1%), Hoarseness (4%), Hypotension (4%), Ileus
> (3%), Incisional pain (5%), Lower extremity weakness (1%), Nausea
> (4%), Near syncope (1%), Neck deformity (1%), Pericardial effusion
> (3%), Pneumothorax (3%), Post-kidney collection (3%), Reintubation
> (1%), Seizure (1%), Sexual dysfunction (1%), Shortness of breath (1%),
> Thrombocytopenia (4%), Thrombophlebitis (1%), Transfusion reaction
> (3%), Urinary retention (1%), Valve surgery (1%), Vocal cord paralysis
> (3%).
>
> > Adverse events were equal in severity in both the BioGlue group and
> > the standard surgical repair group. There were no unanticipated
> > device effects (UADE) in this investigation.

## Device Failures and Replacements

> > No device failures or replacements occurred in the cardiac and
> > vascular arm of the IDE clinical trial.

# Conclusions Drawn from the Studies

## Risk/Benefit Analysis

> > The absence of any significant adverse event related to the use of
> > BioGlue, and the effectiveness of BioGlue in achieving immediate
> > anastomotic hemostasis independent of the body's clotting mechanism
> > and tissue reinforcement in cardiac and vascular repair, attest to
> > the acceptable risk/benefit ratio of BioGlue in sealing cardiac and
> > vascular repair anastomoses.

## Safety

> > The BioGlue Surgical Adhesive implant and accessories demonstrated
> > acceptable biocompatibility in *in vitro* and *in vivo* studies. In
> > the U.S. IDE clinical trial, the absence of any significant adverse
> > events related to BioGlue and similar rates of adverse events for
> > the BioGlue group and standard surgical repair group support the
> > safety of BioGlue in cardiac and vascular repair procedures for
> > sealing anastomoses, providing hemostasis, and reinforcing tissue.

## Effectiveness

> > The results of the preclinical and clinical testing have
> > demonstrated a reasonable assurance of safety and effectiveness for
> > BioGlue for its stated indication for use. A multi-center,
> > randomized controlled trial compared cardiac and vascular repair
> > patients treated with a prophylactic adjunctive BioGlue treatment to
> > a standard surgical repair control group. BioGlue was noted to have
> > a statistically higher rate of intra-operative hemostasis when
> > compared to the control group on both a "per patient" and a "per
> > anastomotic site" basis. BioGlue-treated patients demonstrated a
> > lower incidence of adjunctive pledgets use on their primary repairs
> > to achieve hemostasis. There were no statistical differences in
> > other endpoints, such as blood products or operative times, between
> > study and control patients.

# Panel Recommendations

> To be completed by FDA.

# CDRH Decision

> > To be completed by FDA.
>
> > CDRH issued an approval order on .

# Approval Specifications

> > Direction for Use: See the labeling.
>
> > Hazards to Health from Use of the Device: See indications,
> > Contraindications, Warnings, Precautions, and Adverse Events in the
> > labeling.
>
> > Postapproval Requirements and Restrictions: See approval order.

[^1]: Eddy CA, Choo S, McNally B, Elkins R, Creation and Repair of Acute
    Descending Aortic Dissection in Sheep. Abstract submitted to Aortic
    Surgery Symposium VI. 1998.