Predicate Devices

Not Found

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The summary describes a mechanical device and its bioabsorbable implant. There is no mention of software, algorithms, image processing, or any terms related to AI or ML. The performance studies focus on clinical outcomes and device mechanics, not algorithmic performance.

Therapeutic

Yes

The device is indicated for "closure of the internal opening of mature, cryptogenic, transsphincteric, non-branching fistulas in ano via tissue apposition," which describes a therapeutic intervention. It promotes healing and addresses an existing medical condition.

Diagnostic

No

The device is a therapeutic device (for closure of anal fistulas via tissue apposition) and not a diagnostic device. It is used for treatment, not for diagnosing a condition.

SaMD (Software as a Medical Device)

No

The device description explicitly states that the device comprises a BioHealx Implant and a Delivery System, both of which are physical components. The performance studies also detail testing on these physical components (implant verification, delivery mechanism verification, etc.).

IVD (In Vitro Diagnostic)

Based on the provided information, this device is not an IVD (In Vitro Diagnostic).

Here's why:

Intended Use: The intended use is for the closure of anal fistulas via tissue apposition. This is a therapeutic intervention, not a diagnostic test performed on samples taken from the body.
Device Description: The device is an implant and a delivery system designed to physically close a fistula opening. It does not analyze biological samples to provide diagnostic information.
Lack of Diagnostic Function: There is no mention of the device being used to detect, measure, or analyze substances in vitro (outside the body) for the purpose of diagnosis, monitoring, or screening.
Performance Studies: The performance studies focus on the success of the fistula closure (healing rates, recurrence) and safety (adverse events), which are relevant to a therapeutic device, not a diagnostic one. Metrics like sensitivity, specificity, PPV, and NPV (common for IVDs) are not found.

In summary, the Signum Surgical BioHealx Anal Fistula Device is a surgical device intended for the treatment of anal fistulas, not for in vitro diagnostic testing.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

The BioHealx Anal Fistula Device is indicated as follows:

The Signum Surgical BioHealx Anal Fistula Device is indicated for closure of the internal opening of mature, cryptogenic, transsphincteric, non-branching fistulas in ano via tissue apposition.

Product codes

QML

Device Description

The BioHealx Anal Fistula Device comprises the BioHealx Implant and the Delivery System.

The BioHealx implant is designed as a sterile, single use helical, barbed bioabsorbable implant intended to promote healing by primary intention. The BioHealx delivery device is a sterile single-use, disposable delivery device that rotates the implant into the soft tissue surrounding the internal opening of the fistula tract.

The BioHealx implant apposes the internal opening of the fistula channel and is held in position by its design geometry. The implant is fully enclosed in the anal sphincter muscle tissue and is not exposed to the ano-rectal canal. The implant retains adequate strength to compress the tissue of the internal opening of a fistula for 4 - 6 weeks and is absorbed within 6 - 12 months.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

anal fistula

Indicated Patient Age Range

adults (18 - 75 years)

Intended User / Care Setting

used only by physicians having adequate training and familiarity with the implant technique.

Description of the training set, sample size, data source, and annotation protocol

Human factors validation testing was performed with 10 practicing colorectal surgeons in the US and 7 practicing general surgeons in Europe (Hungary and Ireland). The study utilized a simulated gel model. In addition, a porcine animal study was also implemented with 6 of the users for further validation.

Description of the test set, sample size, data source, and annotation protocol

Not Found

Summary of Performance Studies

Nonclinical/Bench Studies:

Implant Verification Testing: Demonstrated that the BioHealx Implant maintains sufficient strength to support tissue healing for a minimum of 3 weeks post implant delivery. Method: Break strength evaluated at T=0, 3, 4, 6 weeks following simulated in-vitro degradation in buffer solution. Results: All testing passed acceptance criteria.
Delivery Mechanism Verification: Demonstrated that the BioHealx delivery mechanism is capable of successful implant delivery and determined torque requirement to remove an implant from the drive coil assembly. Method: Each test sample was removed from packaging and verified; implant delivered to simulated tissue. Results: All testing passed acceptance criteria.
Implant Migration: Demonstrated resistance to migration / extrusion of the BioHealx implant. Method: BioHealx implant resistance to migration/extrusion evaluated under simulated rectal pressure cycling on BioHealx implant position in an anatomically relevant model. Results: All testing passed acceptance criteria.
Drain Attachment: Demonstrated that the drain capture mechanism is capable of withstanding anticipated loading, allows attachment of 2-0 bioabsorbable suture using a secure knot, and can withstand anticipated loading when attached to suture. Method: Each test sample (Finished Device) was removed from packaging and tested on the bench. Results: All testing passed acceptance criteria.
Drain Release Force: Assessed the force required to release the suture /drain from a delivered BioHealx implant. Method: BioHealx implants delivered to a simulated fistula tract in a representative model. Tensile load applied to each drain to determine detachment force. Results: Average force (95%/95% confidence reliability) required to release the stop knot (3 throws of a figure 8) and to cause the drain to detach was (4) Kg equivalent.
In Vivo Performance Testing (GLP): Evaluated safety and performance of the BioHealx Anal Fistula Device for its intended use in a porcine anal fistula model. Sample Size: Six (6) pigs. Method: Four perianal fistulas created in each animal. After 4-weeks recovery, BioHealx device placed in each fistula tract. Results: All testing passed acceptance criteria. Concluded no evidence of adverse tissue reaction associated with the device in any evaluated samples.
Human Factors/Summative Evaluation Testing: Demonstrated that the components can be used by intended users without serious use errors. Sample Size: 7 x EU, 10 x US representative colorectal surgeons. Method: Participants performed several BioHealx implantations in an anatomically relevant simulated use bench top model. Clinical investigators (N=6) also completed an in vivo simulated use (porcine) animal model (for training effectiveness only). Results: All implanters successfully completed training and evaluation; met objectives to confirm safe and effective delivery; no close calls or use errors observed.
Biocompatibility Testing - Implant: Rabbit Blood Hemolysis Test, 90-Day Systemic Toxicity in Rats via Intramuscular Implantation, 26-week Systemic Toxicity in Rats via Intramuscular Implantation, Intracutaneous Injection Test, Kligman Maximization Test (Sensitization), L929 Neutral Red Uptake Test, Systemic Injection Test, Salmonella Typhimurium and Escherichia Coli Reverse Mutation Assay, Mouse Lymphoma Mutagenesis Assay, Intramuscular Implantation Test for Absorbable/Degradable Materials (2-week and 8-week implantation), Rabbit Pyrogen Test (Material Mediated), BioHealx Implant Endotoxins Test Validation. Results: All tests met acceptance criteria.
Biocompatibility Testing - Delivery System: ISO Guinea Pig Maximization Sensitization Test, Cytotoxicity Study Using the ISO Elution Method, ISO Intracutaneous Irritation Study - Extract, USP Rabbit Pyrogen Study, Material Mediated, ISO Acute Systemic Toxicity Study in Mice. Results: All tests met acceptance criteria.

Clinical Study:

Study Type: Multi-center, prospective, non-randomized clinical study.
Sample Size: 32 patients.
Objective: Evaluate the safety and effectiveness of the BioHealx Anal Fistula Device in adults with recurrent anal fistula. Effectiveness measured by closure repair of the anal fistula (absence of drainage from external opening). Co-primary endpoints: non-recurrence incidence at 6 and 12 months (continued closure of external fistula opening). Safety: review of adverse events.
Key Results:
- By last visit, 59.4% (19/32) of patients were fully healed (external opening scarred over, with no drainage).
- 9.4% (3/32) of patients had an unsuccessful result (recurrence by 12 months).
- 31.2% (10/32) of patients had been downgraded from transsphincteric fistula to either sinus or superficial fistula.
- 28 adverse events in total; one serious (resolved, unrelated to device). 50% (16/32) experienced at least one adverse event (mild or moderate).
- No reports of incontinence, sphincteric damage, severe persistent pain, nerve or vascular injury, device migration or extrusion.
- 71% reduction in mean pain score.
- FIQL scores improved across all four components (7.2% - 11.6% improvement).
- SF-36 Quality of Life outcomes showed positive changes in physical and mental component scores.
- No change in pain medications used during follow-up period (limited to immediate post-surgery).

Key Metrics

Clinical Study (N=32):

Complete Healing (Fistula Closure): 59.4% (19/32) at last visit (external opening scarred over, no drainage).
Unsuccessful Result (Recurrence): 9.4% (3/32) by 12 months.
Downgraded Fistula: 31.2% (10/32) from transsphincteric to sinus or superficial.
Absence of Incontinence: 100% (No reports).
Absence of Device Migration/Extrusion: 100% (No reports).
Reduction in Mean Pain Score: 71% (Wong-Baker FACES®).
Improvement in FIQL Scores: 7.2% - 11.6% across four components.
Adverse Event Rate: 50% (16/32 patients experienced at least one AE).
Serious Adverse Events: 1 (resolved, unrelated to device).

Predicate Device(s)

Not Found

Reference Device(s)

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information

Not Found

Regulation Number and Section

N/A

Summary

0

DE NOVO CLASSIFICATION REQUEST FOR BIOHEALX ANAL FISTULA DEVICE

REGULATORY INFORMATION

FDA identifies this generic type of device as:

Anal fistula closure device. An anal fistula closure device is a surgical implant for anal fistula repair and is intended for closure of the anal fistula. The device may be manually applied or delivered with a delivery device.

NEW REGULATION NUMBER: 21 CFR 878.4835

CLASSIFICATION: Class II

PRODUCT CODE: QML

BACKGROUND

DEVICE NAME: BioHealx Anal Fistula Device

SUBMISSION NUMBER: DEN240007

DATE DE NOVO RECEIVED: February 2, 2024

SPONSOR INFORMATION:

Signum Surgical Limited Galway Harbour Enterprise Park, New Docks, The Docks Galway H91 NNY6 Ireland

INDICATIONS FOR USE

The BioHealx Anal Fistula Device is indicated as follows:

The Signum Surgical BioHealx Anal Fistula Device is indicated for closure of the internal opening of mature, cryptogenic, transsphincteric, non-branching fistulas in ano via tissue apposition.

LIMITATIONS

The sale, distribution, and use of the BioHealx Anal Fistula Device are restricted to prescription use in accordance with 21 CFR 801.109.

Contraindications

1

The BioHealx Anal Fistula Device should only be used for the repair of anal fistulas.
. This device should not be used in tissues that have a direct anatomic relationship to major vascular structures.

Key Limitations

The BioHealx Anal Fistula Device should be used only by physicians having adequate ● training and familiarity with the implant technique.
The BioHealx implant is suitable only for use in fistulas of any length greater than 2cm. ●
The BioHealx device has not been evaluated in patients with Crohn's disease. ●
The device should not be used in pregnant women. ●
The device should not be used in patients with a known allergy to poly (lactic-co-glycolic acid), (PLGA).
Do not attempt anterior delivery in females, to prevent implant penetration through the vaginal wall.
Do not deliver at external opening of fistula tract.
Remove implant if not completely delivered. ●

PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.

DEVICE DESCRIPTION

The BioHealx Anal Fistula Device comprises the BioHealx Implant and the Delivery System.

The BioHealx implant is designed as a sterile, single use helical, barbed bioabsorbable implant intended to promote healing by primary intention. The BioHealx delivery device is a sterile single-use, disposable delivery device that rotates the implant into the soft tissue surrounding the internal opening of the fistula tract.

The BioHealx implant apposes the internal opening of the fistula channel and is held in position by its design geometry. The implant is fully enclosed in the anal sphincter muscle tissue and is not exposed to the ano-rectal canal. The implant retains adequate strength to compress the tissue of the internal opening of a fistula for 4 - 6 weeks and is absorbed within 6 - 12 months.

BioHealx Implant

The BioHealx implant is designed as a coil, with a tapered inner surface. The coil design facilitates insertion around the fistula tract lumen at the internal opening. The sphincter muscle tissue surrounding the fistula internal opening is gathered and compressed by the implant's internal taper geometry during implant delivery, effecting closure of the internal opening by direct tissue apposition.

2

Image /page/2/Figure/0 description: The image shows a 3D rendering of a medical device. The device has a cylindrical shape with barbs protruding from the surface. The text labels indicate the presence of barbs and a tapered internal lumen.

Figure 1 Signum Surgical BioHealx™ Anal Fistula implant.

The anti-rewind features ("barbs") (Figure 1) at the outer perimeter of the implant serve as retention features to prevent the device migration/extrusion once implanted. The implant is centered around the fistula tract at the internal opening in the sphincter muscle complex, causing the fistula to close within the tapered internal lumen of the implant.

Degradation

The constituent implant material is poly (lactic-co-glycolic acid), (PLGA). Poly (lactic-coglycolic acid), (PLGA) is a material that degrades by hydrolysis (i.e., degradation takes place in the presence of water).

The progression of the absorption process proceeds from loss of mechanical strength followed by loss of physical structural integrity marked by fragmentation followed by breakdown to microscopic residue and ultimate elimination from the body. Non-clinical bench testing (invitro) found that the loss of physical structural integrity has occurred by week 26 (6 months). Biocompatibility testing (26-week implantation study) found that only test article fragments (i.e., mostly degraded) could be identified.

BioHealx Delivery System

The BioHealx implant is delivered to the operative site by means of a single-use disposable delivery device (Figure 2) that is preloaded with the implant (Figure 3). The BioHealx delivery system controls the positioning and depth of delivery of the implant, standardizing the procedure and reducing operator variability.

3

Image /page/3/Figure/0 description: The image shows a medical device with a white handle and a curved metal tip. The device has a gray knob at the end, followed by a green lock. The text labels in the image identify the different parts of the device, including the device handle, knob, and lock.

Figure 2 Signum Surgical BioHealx Anal Fistula delivery system.

Image /page/3/Picture/2 description: The image shows a close-up of two metal tools with a spiral cutting edge. The tools are silver in color and have a cylindrical shape. The cutting edge is made up of a series of small, sharp teeth that are arranged in a spiral pattern. The tools appear to be used for cutting or drilling materials, and the spiral cutting edge helps to remove material as the tool rotates.

on Driver Coil

Image /page/3/Picture/3 description: The image shows a CAD rendering of a curved pipe with a transparent section revealing an internal helix structure. An additional helix component is detached and positioned to the right of the pipe's opening. The pipe is light gray, while the detached helix is a darker shade of blue.

(a) Photographic Image of Implant loaded (b) 3-Dimensional Model of Implant detached from Driver Coil

Figure 3 BioHealx implant preloaded to BioHealx delivery system.

A stainless-steel wire suture attachment loop extends 3mm to 5mm beyond the distal end of the device (see Figure 4). The suture attachment loop provides an easy access point allowing the user to attach a commercially available USP size 2-0, braided, coated synthetic absorbable suture for delivery device guidance prior to implant delivery. The suture attachment loop is attached internally to the lock component at the proximal end of the delivery device and is retracted with the lock retraction prior to implant delivery.

4

Image /page/4/Figure/0 description: The image shows a medical device with several labeled parts. The parts labeled are the device handle, lock, knob, shaft, and suture attachment loop. There is also a close up of the suture attachment loop with a suture attached.

Figure 4 BioHealx Delivery System with Suture Attachment Wire Loop

Turning the delivery system knob clockwise (three full turns) rotates the implant driver coil clockwise to deliver the helical implant circumferentially to surround the internal opening of the fistula to the predefined depth controlled by the driver coil. The internal drive mechanism has a one-way ratchet to ensure the user deploys the device fully; a series of audible clicks will be heard during the knob rotation. After the implant is fully delivered the knob can no longer be turned ('bottoms out'), signaling to the user to begin retraction via counterclockwise rotation of the knob. The barbs (Figure 1) that radially extend from the implant provide anchorage in the tissue releasing the implant from the driver coil and leaving the implant to remain surrounding the internal opening of the fistula tract. Once the driver coil is retracted, the user removes the delivery device from the patient.

SUMMARY OF NONCLINICAL/BENCH STUDIES

Non-clinical/Bench studies conducted on the BioHealx Anal Fistula Device demonstrate safety and effectiveness and are summarized below.

Test	Purpose	Method	Acceptance Criteria	Results
Implant
Verification
Testing	Demonstrate that the
BioHealx Implant
maintains sufficient
strength to support
tissue healing for a
minimum of 3 weeks
post implant delivery (a
strength equal to or
greater than (b) (4)	The break strength
was evaluated at T=0,
3, 4, 6 weeks
following simulated
in-vitro degradation in
buffer solution at
(b) (4)	Tensile (implant break)
strength must be (b) (4)
(T=0) and (b) (4) (T=3
weeks, 4 weeks, 6 weeks).	All testing
passed the
acceptance
criteria.
Delivery
Mechanism
Verification	Demonstrate that the
BioHealx delivery
mechanism is capable
of successful implant
delivery.
Determine the torque
requirement to remove	Each test sample
(Finished Device) was
removed from the
packaging and verified
to meet specifications.
The BioHealx implant
was delivered to
between (b) (4)	a) The BioHealx Anal
Fistula Device must be
capable of consistent
successful delivery of
the BioHealx implant,
to a controlled depth,
being delivered to
simulated tissue.	All testing
passed the
acceptance
criteria.
Test	Purpose	Method	Acceptance Criteria	Results
	an implant from the
drive coil assembly
(implant lock testing).	into the simulated
tissue surface.	b) The drain capture
mechanism must be
capable of withstanding
a (b) (4) load without
failure and allow
attachment of USP size
2-0 bioabsorbable
suture via a secure knot.
c) The implant must
maintain integrity and
form (geometry) post
implant delivery.
Implant
Migration	Demonstrate resistance
to migration / extrusion
of the BioHealx
implant.	The BioHealx implant
resistance to
migration/extrusion
was evaluated under
the conditions of
simulated rectal
pressure cycling on
BioHealx implant
position.
All bench testing was
performed in an
anatomically relevant
model.	a) The applied force
required to cause implant
migration and extrusion
force in the gel model
must be (b) (4) axial
force (b) (4)
b) The BioHealx implant
final position (post
pressure cycling) must
remain within the
required delivery depth
specification of (b) (4)
(b) (4)	All testing
passed the
acceptance
criteria.
Drain
Attachment	Demonstrate that the
drain capture
mechanism is:

Capable of
withstanding
anticipated loading
Allows attachment of
2-0 bioabsorbable
suture using a secure
knot.
When attached to
suture (drain
capture/suture
assembly) can
withstand anticipated
loading while (i)
retracting the lock
and (ii) post
retraction of lock. | Each test sample
(Finished Device) was
removed from the
packaging and tested
on the bench to ensure
that the drain capture
mechanism could
withstand the
anticipated loading. | a) Drain capture mechanism
must withstand an
applied load (b) (4)
without failure.
b) Drain capture
mechanism shall allow
attachment of 2-0
bioabsorbable suture
using a secure knot.
c) Drain capture/ suture
assembly must
withstand an applied
(b) (4) load while
(i) retracting the lock
and (ii) post retraction
of lock. | All testing
passed the
acceptance
criteria. |
| Test | Purpose | Method | Acceptance Criteria | Results |
| Drain Release
Force | Assessment of the force
required to release the
suture /drain from a
delivered BioHealx
implant. | BioHealx implants
were delivered to a
simulated fistula tract
in a representative
model. For each
fistula tract/implant
delivered, a simulated
drain using suture
material was created.
A tensile load was
applied to each drain
to determine the force
required to cause
detachment. | This testing was used to
collect representative data to
determine the force required
to release the suture/drain
from a delivered BioHealx
implant. | The average
force (95%/95%
confidence
reliability)
required to
release the stop
knot (3 throws
of a figure 8)
and to cause the
drain to detach
was
(4) Kg equivalent.) |
| In Vivo
Performance
Testing (GLP) | Evaluate the safety and
performance of the
BioHealx Anal Fistula
Device for its intended
use to appose tissues in
the repair of anal
fistulas using a porcine
anal fistula model. | Cohort of six (6) pigs
(species strain Sus
scrofa scrofa/
domestic. Yorkshire
cross – white) were
treated in the study.
Four perianal
fistulas, with a
seton placed, were
created at the 3,5,7
and 9 o'clock
positions in each
animal.
After 4-weeks
recovery, a second
surgical procedure
was performed per
the BioHealx
implant procedure.
This involved the
creation of a small
mucosal incision
at the internal
opening site, and
partial
fistulectomy as
necessary
followed by
placement of the
BioHealx device
in each of the
fistula tracts. | Animals were observed for
any adverse clinical signs of
disease or ill health.

Fistula healing, as assessed
by histopathology analysis.
Determine that the
BioHealx device does not
adversely affect the
incidence and rate of
perianal healing nor have
any detrimental effect as
determined by
histopathology). | All testing
passed the
acceptance
criteria.

Testing
concluded that
there was no
evidence of
adverse tissue
reaction
associated with
the BioHealx
device in any of
the evaluated
samples. |
| Human Factors/
Summative
Evaluation
Testing | Demonstrate the
components of the
BioHealx system can be
used by the intended
users without serious
use errors or problems, | Users: 7 x EU, 10 x
US representative
colorectal surgeons.

Confirm that the
BioHealx device
can be safely
delivered.
Confirm that the
BioHealx device
can be effectively
delivered.
Confirm no
unanticipated
serious use errors
attributable to the
system user
interfaces.
Evaluate the
simulated model as
an effective
training tool for
BioHealx system
users. | several BioHealx
implantations in an
anatomically relevant
simulated use bench
top model.

Clinical investigators
(N=6) also completed
an in vivo simulated
use (porcine) animal
model.

Note: The human
factors simulated use
in vivo testing was for
training effectiveness
evaluation only and
was a separate activity
to the GLP in vivo
performance testing
(described above). | without damage to the
device (e.g., drop
device)
c) User feedback on the
tissue stabilization
features must not
identify
risks/complaints.
d) User must not cut
gloves/cause self-injury
during device use.
e) User must successfully
attach suture to the
device attachment loop.
f) User must successfully
place speculum and
must not complain
about device interface
experience with
speculum. | The objectives to
confirm that the
BioHealx device
can be safely and
effectively
delivered were
met.

There were no
close calls or use
errors observed
during the
evaluation.

The simulated
use model was
demonstrated to
be an effective
training tool. |
| Biocompatibility
Testing -
Implant.

Rabbit Blood
Hemolysis Test. | To determine the
potential hemolytic
activity, via the
induction of increased
levels of free plasma
hemoglobin in rabbit
blood, in response to
the BioHealx implant
test article and its
extract. | ASTM F756,
ISO 10993-12,
ASTM F619 | Acceptance criteria per ISO
10993-4 (2017), ISO 10993-
12 (2012), ASTM F756-17,
ASTM F619-14. | All testing met
the acceptance
criteria. The
BioHealx
implant was
determined to be
non-hemolytic. |
| Biocompatibility
Testing -
Implant.

90-Day
Systemic
Toxicity in Rats
via
Intramuscular
Implantation. | To determine the
toxicity potential of a
test material
administered by muscle
implantation in rats for
90-days. | ISO 10993-6 (2016),
ISO 10993-11 (2017),
OECD 408, ISO
10993-12 (2012). | Acceptance criteria per ISO
10993-6 (2016), ISO 10993-
11 (2017), OECD 408, ISO
10993-12 (2012). | All testing met
the acceptance
criteria. The
BioHealx
implant did not
demonstrate any
local or systemic
signs of toxicity
when implanted
in rats for 90-
days. |
| Biocompatibility
Testing -
Implant.

26-week
Systemic
Toxicity in Rats
via | To determine the
toxicity potential of a
test material
administered by muscle
implantation in rats for
26-weeks. | ISO 10993-6 (2016),
ISO 10993-11 (2017),
OECD 408, ISO
10993-12 (2012). | Acceptance criteria per ISO
10993-6 (2016), ISO 10993-
11 (2017), OECD 408, ISO
10993-12 (2012). | All testing met
the acceptance
criteria. The
BioHealx
implant did not
demonstrate any
local or systemic
signs of toxicity
when implanted
in rats for 26-weeks. |
| Test | Purpose | Method | Acceptance Criteria | Results |
| Intramuscular
Implantation. | | | | in rats for 26
weeks. |
| Biocompatibility
Testing -
Implant.
Intracutaneous
Injection Test -
ISO | To determine the
potential irritation
effects of the BioHealx
implant test article
extract after
intracutaneous injection
in New Zealand White
rabbits | ISO 10993-10 (2010),
ISO 10993-12 (2012). | Acceptance criteria, per ISO
10993-10 (2010), ISO
10993-12 (2012). | All testing met
the acceptance
criteria.
The BioHealx
test article met
the requirements
of the ISO
10993-10. |
| Biocompatibility
Testing -
Implant.
Kligman
Maximization
Test – ISO
(Sensitization) | To determine the
potential allergenic or
sensitizing capacity of
the BioHealx test
article. | ISO 10993-10 (2010),
ISO 10993-12 (2012). | Acceptance criteria per ISO
10993-10 (2010), USP 141,
ISO 10993-12 (2012). | The BioHealx
test article met
the requirements
of the ISO
10993-10.
All testing met
the acceptance
criteria. |
| Biocompatibility
Testing -
Implant.
L929 Neutral
Red Uptake Test
(4 Conc'ns) -
ISO | To determine the
potential biological
reactivity of a
mammalian cell culture
(L929) in response to
the BioHealx implant
test article extract. | ISO 10993-11 (2017),
ISO 10993-12 (2012). | Acceptance criteria per ISO
10993-5 (2009), ISO 10993-
12 (2012). | All testing met
the acceptance
criteria.
The BioHealx
test article met
the requirements
of ISO 10993-5. |
| Biocompatibility
Testing –
Implant.
Systemic
Injection Test -
ISO | To determine the
potential toxic effects
of the BioHealx implant
test article extract as a
result of a single-dose
systemic injection in
mice. | ISO 10993-11 (2017),
ISO 10993-12 (2012). | Acceptance criteria per ISO
10993-11 (2017), ISO
10993-12 (2012) | All testing met
the acceptance
criteria.
The BioHealx
test article met
the requirements
of ISO 10993-
11. |
| Biocompatibility
Testing -
Implant.
Salmonella
Typhimurium
and Escherichia
Coli Reverse
Mutation Assay

ISO | To determine the
potential mutagenicity
of the BioHealx implant
test article extract on
various strains of
Salmonella
typhimurium (S.
typhimurium) and
Escherichia coli (E.
coli) bacteria, via a
change in their
dependence for
histidine or tryptophan. | ISO 10993-3, 2014
ISO/TR 10993-33,
2015
OECD 471
ISO 10993-12, 2012, | Acceptance criteria per ISO
10993-3(2014), ISO/TR
10993-33 (2015), Part 33,
OECD 471, ISO 10993-12
(2012). | All testing met
the acceptance
criteria.
The BioHealx
implant test
article was found
to be non-
mutagenic. |
| Biocompatibility
Testing -
Implant.
Mouse
Lymphoma | To determine the
potential mutagenicity
effect on mouse
lymphoma cells
(heterozygous
thymidine kinases | ISO 10993-3 (2014),
ISO 10993-33 (2015),
OECD 490, ISO
10993-12 (2012). | Acceptance criteria per ISO
10993-3 (2014), ISO 10993-
33 (2015), OECD 490, ISO
10993-12 (2012). | All testing met
the acceptance
criteria.
The BioHealx
implant test |
| Test | Purpose | Method | Acceptance Criteria | Results |
| Mutagenesis
Assay - ISO | mutant TK(+L5178Y) in
response to the
BioHealx implant test
article extract. | | | article was found
to be non-
mutagenic. |
| Biocompatibility
Testing -
Implant.
Intramuscular
Implantation
Test for
Absorbable/Deg
radable
Materials - ISO
2-week
implantation | To evaluate the
BioHealx implant test
article for local tissue
responses and the
potential to induce local
toxic effects after
implantation (for 2-
weeks) in the muscle
tissue of albino rabbits.
Absorption of the test
article was assessed. | ISO 10993-6 (2016),
10993-12 (2012). | Acceptance criteria per ISO
10993-6 (2016), 10993-12
(2012). | All testing met
the acceptance
criteria.
The BioHealx
implant test
article was
considered non-
reactive and met
the requirements
of ISO 10993-6. |
| Biocompatibility
Testing -
Implant.
Intramuscular
Implantation
Test for
Absorbable/
Degradable
Materials - ISO
8-week
implantation | To evaluate the
BioHealx implant test
article for local tissue
responses and the
potential to induce local
toxic effects after
implantation (for 8-
weeks) in the muscle
tissue of albino rabbits.
Absorption of the test
article was assessed. | ISO 10993-6 (2016),
10993-12 (2012). | Acceptance criteria per ISO
10993-6 (2016), 10993-12
(2012). | All testing met
the acceptance
criteria.
The BioHealx
implant test
article was
considered non-
reactive and met
the requirements
of ISO 10993-6. |
| Biocompatibility
Testing -
Implant.
Rabbit Pyrogen
Test (Material
Mediated) - ISO | To determine the
potential presence of
chemical pyrogens in
extracts of solid
materials in order to
limit to an acceptable
level the risk of febrile
reaction following
administration of the
BioHealx implant
(product) to a patient. | ISO 10993-11 (2017),
10993-12 (2012). | Acceptance criteria per ISO
10993-11 (2017), 10993-12
(2012). | All testing met
the acceptance
criteria.
The results
supported that
the BioHealx
implant is non-
pyrogenic and
meets the
requirements of
the Pyrogen
Test, ISO
10993-11. |
| BioHealx
Implant
Endotoxins Test
Validation | To validate the gel clot
lysate method for
endotoxin testing | 10993-12 (2012). | Study was conducted based
on USP 41, NF 36 (2018),
Bacterial Endotoxins
Test, 10993-12 (2012). | The test articles,
Signum Surgical
BioHealx, meet
the requirements
of the
Amoebocyte
Lysate
Endotoxin
Validation Test,
Gel Clot Method |
| Test | Purpose | Method | Acceptance Criteria | Results |
| | | | | according to the
USP guidelines.
The test articles
do not inhibit or
enhance the
assay. |
| | | | | All testing met
the acceptance
criteria. |
| BioHealx
Delivery System
ISO Guinea Pig
Maximization
Sensitization
Test | To evaluate the
potential of the
BioHealx Delivery
Device test article
extract to cause delayed
dermal contact
sensitization in the
guinea pig
maximization test. The
Magnusson and
Kligman method has
been effective in
identifying a variety of
allergens. | 10993-10 (2021),
10993-12 (2021) | Acceptance criteria per ISO
10993-10 (2021), 10993-12
(2021). | All testing met
the acceptance
criteria.

The BioHealx
Delivery System
test article was
not considered a
sensitizer in the
guinea pig
maximization
test. |
| BioHealx
Delivery System
Cytotoxicity
Study Using the
ISO Elution
Method | To determine the
potential of a test article
extract to cause
cytotoxicity. | ISO 10993-5 (2009),
10993-12 (2021). | Acceptance criteria per ISO
10993-5 (2009), 10993-12
(2021). | All testing met
the acceptance
criteria.

The BioHealx
Delivery System
test article
extract showed
no evidence of
causing cell lysis
or toxicity. |
| BioHealx
Delivery System
ISO
Intracutaneous
Irritation Study-
Extract | To evaluate the local
dermal irritation of a
test article extract
following
intracutaneous injection
in rabbits. | 10993-23 (2009),
10993-12 (2021). | Acceptance criteria per ISO
10993-23 (2009), 10993-12
(2021). | All testing met
the acceptance
criteria.

The BioHealx
Delivery System
test article
showed no
evidence of
causing
irritation. |
| BioHealx
Delivery System
USP Rabbit
Pyrogen Study,
Material
Mediated | To determine whether
an extract of the test
article induced a
pyrogenic response
following intravenous
injection in rabbits. | USP
ISO 10993-11 (2017),
10993-12 (2021). | Acceptance criteria per USP
, Pyrogen Test, ISO
10993-11 (2017), 10993-12
(2021). | All testing met
the acceptance
criteria.

The BioHealx
Delivery System
test article met
the requirements |
| Test | Purpose | Method | Acceptance Criteria | Results |
| | | | | for the absence
of pyrogens. |
| BioHealx
Delivery System
ISO Acute
Systemic
Toxicity Study
in Mice | To evaluate the acute
systemic toxicity of a
test article extract
following injection in
mice. | ISO 10993-11 (2017),
10993-12 (2021). | Acceptance criteria per ISO
10993-11 (2017), 10993-12
(2021). | All testing met
the acceptance
criteria. |
| | | | | The BioHealx
Delivery System
test article
showed no
mortality or
evidence of
systemic toxicity
from the extracts
injected into
mice. |

Table 1

5

6

7

8

9

10

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BIOCOMPATIBILITY/MATERIALS

The BioHealx Anal Fistula Device components were classified as follows for the purpose of performing biocompatibility testing per ISO 10993 and FDA Guidance on the "Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process" (September 2020) as described below. Based on the outcomes of the biocompatibility evaluation, the BioHealx Anal Fistula Device Implant and Delivery System patient contacting components are considered biocompatible.

BioHealx Implant

The BioHealx implant is a permanent implant (> 30 days), absorbable device having direct contact with patient tissue. Degradation information was addressed in the implantation testing, sub-chronic/chronic toxicity testing and the in vivo performance (animal) study. Carcinogenicity was addressed through a toxicological risk assessment.

Biocompatibility endpoints were addressed through ISO standard testing for the BioHealx implant including:

Cytotoxicity
Sensitization
Irritation Testing, Intracutaneous reactivity ●
Acute systemic toxicity ●
Material mediated pyrogenicity ●
Genotoxicity
Implantation ●
Hemocompatibility ●
Chronic Toxicity (26- weeks) ●

All tests met their test requirements.

BioHealx Delivery System

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The BioHealx Anal Fistula Device delivery system is an external communicating device having limited contact ( 18 undergoing elective treatment for a persistent anal fistula.

Demographics and Baseline Data: 32 patients with recurrent transsphincteric fistula were implanted with BioHealx Anal Fistula Device. The mean age was 49.9 years (33 - 76 years). 84.5% of patients were male, 15.6% were female and 96.9% were Caucasian. The mean BMI was 28.15 kg/m2 (18.8 - 41.5). The mean baseline pain score was 2.00 (range 0 - 8). Patient demographics and medical history are shown in Table 2 and Table 3 respectively.

Characteristic	BioHealx (N=32)
Gender: n/N (% Male)	27/32 (84.4%)
Age: Mean, Median, Std. Deviation
(Min, Max)	49.9, 49.0, 11.61,
(33, 76)
Height (cm): Mean, Median, Std. Deviation
(Min, Max)	176.3, 176.0, 8.73,
(158.0, 190.0)
Weight (kg): Mean, Median, Std. Deviation
(Min, Max)	87.2, 88.5, 15.70,
(53, 120)
BMI (kg/m2): Mean, Median, Std. Deviation
(Min, Max)	28.15, 28.52, 5.369,
(18.8, 41.5)
Ethnicity: White	31/32 (96.9%)
Ethnicity: Black	0/32 (0%)
Ethnicity: Asian	0/32 (0%)
Ethnicity: Hispanic	0/32 (0%)
Ethnicity: Other	1/32 (3.1%)

Table 2 Baseline Demographics and Characteristics

Table 3 Summary of Medical History

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BioHealx Study (N=32)
Medical History	Yes
(n/N, %)	No
(n/N, %)	Unknown
(n/N, %)
Anemia	0/32 (0.0%)	32/32 (100%)	0/32 (0.0%)
Diabetes	3/32, (9.4%)	29/32, (90.6%)	0/32 (0.0%)
Congestive Heart Failure (CHF)	0/32 (0.0%)	31/32, (96.9%)	1/32, (3.1%)
Hypertension	14/32, (43.8%)	18/32, (56.3%)	0/32 (0.0%)
Coagulation Abnormality	0/32 (0.0%)	32/32 (100%)	0/32 (0.0%)
COPD	0/32 (0.0%)	32/32 (100%)	0/32 (0.0%)
Obesity
(> 150 % of ideal weight)	5/32, (15.6%)	27/32, (84.4%)	0/32 (0.0%)
	Smoker	6/32, (18.8%)	26/32 (81.3%)
Current active abscess or infection	0/32 (0.0%)	32/32 (100%)	0/32 (0.0%)
Other significant condition	7/32, (21.9%)	25/32, (78.1%)	0/32 (0.0%)

The 7 clinical subjects with at least an "other significant condition" (coded by MedDRA, SOC) were as follows: Cardiac Disorders: 1/32 (3.1%) with a cardiac atrial fibrillation; Endocrine Disorders: 1/32 (3.1%) with hypothyroidism; Gastrointestinal Disorders: 2/32, (6.3%) gastroesophageal reflux disease; Metabolism and Nutrition Disorders: 2/32, (6.3%); Nervous System Disorders: 1/32, (3.1%) with epilepsy; and Vascular Disorders: 2/32, (6.3%) with hypertension.

Characteristic	BioHealx (N=32)
Type of Fistula: Trans-sphincteric	32/32 (100%)
Est. Length of Fistula Tract (cm):
Mean	4.42
Median (Min, Max)	4.00 (2.50 - 8.00)
No. of Fistula Openings: n/N (%)
Internal 1 opening:	32/32 (100%)
External 1 opening:	32/32 (100%)
External 2 openings:	0/32 (0%)
Recurrent Fistula: n/N (%)	32/32 (100%)
Pain a
Mean (Min. Max)	2.00 (0-8)

Table 4 Fistula Variables at Baseline

a Pain Scale: 0-10 (0=No pain, 5=Moderate pain, 10=Worst pain)

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100% of clinical subjects had at least one previous treatment (failed) for the anal fistula for which they had enrolled in the study.

Effectiveness Endpoints: The primary effectiveness of the Signum Surgical BioHealx™ Anal Fistula Device measured by successful closure repair of the anal fistula as determined by absence of drainage from the external opening site. Co-primary endpoints were defined as non-recurrence incidence at 12 months as determined by continued closure of the external fistula opening. Secondary effectiveness endpoints included:

. Fecal incontinence score at each follow-up visit
. Quality of life data collected at each follow-up visit
. Pain scores recorded at each follow-up visit
Analgesic and antibiotic use after the surgery and at each follow-up visit .
. Healing analysis: detailed information on changes in fistula condition and the type of any observed discharge/drainage at each follow-up visit.

Safety Endpoints: Safety endpoints included the evaluation of any presence and persistence of anal fistula as it is associated with significant morbidity. In addition to a high risk of recurrence, the condition can result in abscesses, local and systemic infection, fever, itching and bleeding. Various medications are prescribed to alleviate these complications and their symptoms.

. All reports of adverse events were recorded whether deemed to be device-related or not.
Incidence, severity, and persistence of adverse events were to be tabulated and compared to such rates as reported in the literature for other anal fistula treatments.

Medication use was recorded and as applicable, tabulated against rate of usage as reported in the literature for other fistula treatments.

Follow-Up Schedule: Post-treatment follow-up visits occurred at 1-week, 1-months, 6months, and 12-months. To collect longer term data, patients were reconsented to attend an additional post-12-month follow-up visit. At each post-treatment follow-up visit, the following data was collected:

Vital signs (blood pressure, heart rate, body temperature)
Presenting symptoms (pain, fecal incontinence, infection),
Patient reported health status (SF-36 Form, Fecal Incontinence, FACES Pain), ●
Presence of bleeding/fistula discharge,
Antibiotic and immunosuppressant use and any other medications (e.g., pain medications)
Presence Suture Drain ●
Extent of Closure repair (Observational)
. Extent of Closure repair/Fistula Closure (from 6-month post treatment visit only, flush test, if applicable)

Adverse Events, Adverse Device EventsPatient perspectives data was collected, via questionnaire, at the post 12-month follow-up visit.

Subject Accountability: All 32 patients were followed for a minimum of 12-months; 18 (of 32) patients, presented for a post 12-month follow-up visit to provide post-implant data of up to 40months (average 23.4 months).

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Clinical Results: By the last visit, 59.4% (19/32) of patients were fully healed (external opening scarred over, with no drainage). Of the 32 patients, 9.4% (3/32) of patients had an unsuccessful result, i.e., recurrence of the original treated fistula. All recurrent fistulas had occurred by 12months.

An additional 31.2% (10/32) of patients had been downgraded from transsphincteric fistula to either sinus or superficial fistula. Downgrading of the fistula is defined as conversion from transsphincteric fistula to superficial fistula or sinus, which may undergo a secondary treatment (e.g., fistulotomy or silver nitrate) to promote transition to fully scarred over.

There were 28 adverse events in total, one of which was considered serious (resolved) and no unanticipated or serious adverse device related events. 50% (16/32) of clinical subjects experienced at least one adverse event; adverse events have been reviewed and found to be classified as either mild or moderate. There was one serious adverse event reported (resolved), identified as unrelated to the BioHealx device. The serious adverse event was reported as wound bleeding at the outer site of the partial fistulectomy.

From baseline to the last visit:

There were no reports of incontinence, sphincteric damage, severe persistent pain (FACES-. WONG >4), nerve or vascular injury, device migration or extrusion.
There was a 71% reduction in mean pain score (10-point Wong-Baker FACES®) when ● compared to baseline.
. FIQL scores improved across all four components (lifestyle, coping behavior, depression/self-perception and embarrassment); the increases ranged from 7.2% - 11.6% improvement in quality-of-life score when compared to baseline.
. SF-36 Quality of Life outcomes showed indications of positive (improved quality of life scores) changes in physical component score (increase from 59.93±0.876 (postsurgery/hospital discharge) to 60.66±0.424 (at 12-months)) and mental component scores (59.51±0.941 (post-surgery/hospital discharge) to 59.83±0.991 (12 months)).
There was no change in pain medications used by the study cohort during the follow-up period; pain medication use was limited to the immediate post-surgery period only.

Pediatric Extrapolation

The BioHealx Anal Fistula Device is indicated for patients aged 18 and older. For medical devices, the FD&C Act defines patients before their 22nd birthday as pediatric patients. It was appropriate to indicate the device for individuals 18 and older because patients aged 18 - 21 do not carry additional differences or risks relative to the patient population.

LABELING

Labelling has been provided including the instructions for use and package labels. The labelling meets the requirements of 21 CFR 801.109 for prescription devices and includes a description of the device, information for use including indications, methods, hazards, contraindications and precautions under which practitioners licensed to administer the device can use safety and for the purpose for which it is intended. A summary of the clinical validation data provides expected performance for intended use populations. Other patient conditions that may affect performance of the device are listed in the labelling.

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RISKS TO HEALTH

The table below identifies the risks to health that may be associated with the use of the anal fistula closure device and the measure necessary to mitigate these risks.

Identified Risks to Health	Mitigation Measures
Product failure or malfunction Inability to deliver the implant Recurrence Extrusion / migration Lack of fistula closure	Clinical performance testing
Postmarket surveillance
Non-clinical performance testing
Animal performance testing
Shelf life testing
Labeling
Adverse tissue reaction	Animal performance testing
Non-clinical performance testing
Biocompatibility evaluation
Labeling
Infection	Clinical performance testing
Postmarket surveillance
Animal performance testing
Sterilization validation
Shelf life testing
Labeling
Adverse events associated with improper
device use or fistula repair and subsequent
sequelae, including: Fecal incontinence Perirectal abscess Tissue trauma during device placement Bleeding Pain	Clinical performance testing
Postmarket surveillance
Animal performance testing
Non-clinical performance testing
Labeling

SPECIAL CONTROLS

In combination with the general controls of the FD&C Act, the anal fistula closure device is subject to the following special controls:

(1) Premarket clinical performance testing and postmarket surveillance acquired under anticipated conditions of use must demonstrate that the device performs as intended in the intended patient population unless FDA determines based on the totality of the information provided for premarket review that data from postmarket surveillance is not required. Testing must:
- Demonstrate the ability to deliver the device to the fistula site; (i)
- Demonstrate the ability to achieve fistula closure of both the internal and (ii) external openings with absence of drainage:
- (iii) Assess safety endpoints including tissue trauma, migration/extrusion, infection, perirectal abscess, bleeding, incontinence of stool or flatus, and pain; and

21

(iv) Assess fistula healing and recurrence, time to healing, surgical time required, and number of re-operative procedures needed to completely heal the fistula, including any need for seton maturation of the fistula.
(2) Animal performance testing must demonstrate that the device performs as intended under anticipated conditions of use. Testing must assess histopathology, device migration/extrusion, infection, surgical time required, and tissue integration.
(3) Non-clinical performance testing must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be evaluated:
- Materials characterization of all components, including physical characteristics (i) and compositional identity and purity:
- (ii) Mechanical strength of the implant;
- (iii) Mechanical integrity and functionality of any delivery systems; and
- (iv) For absorbable devices:
  - (A) Residual strength over a clinically relevant timeframe; and
  - (B) Evaluation of absorption at clinically relevant timepoints.
(4) The device must be demonstrated to be biocompatible.
(5) Performance data must demonstrate the sterility of the device.
(6) Performance data must support the shelf life of the device by demonstrating continued sterility, package integrity, and device functionality over the identified shelf life.
(7) Labeling must include:
- The material composition, including any dyes or coatings; (i)
- A detailed summary of the clinical performance testing conducted with the (ii) device, including device- and procedure-related adverse events;
- (iii) An expiration date or shelf life: and
- (iv) A detailed summary of the postmarket surveillance data collected and any necessary modifications to the labeling to accurately reflect outcomes based upon the postmarket surveillance data collected.

BENEFIT-RISK DETERMINATION

The risks of the device are based on data collected in the nonclinical in vivo study in addition to the clinical study described above. The risks and benefits of Signum Surgical's BioHealx Anal Fistula Device have been considered using the- Ligation of the Inter-sphincteric Fistula Tract (LIFT) surgical procedure as a frame of reference, particularly in the context of fistula persistence, recurrence, and procedure related sphincter damage/incontinence.

There are several existing treatment options including surgical fistulotomy, cutting seton, advancement flap procedure. LIFT procedure. A common complication of anal fistula surgery is the persistence or recurrence of the pathology, both considered a failure of surgery. Recurrent

22

anal fistulas, after previous surgery, represent an increasingly challenging problem since they are usually associated with a higher risk of re-recurrence and continence disturbance. Alternate options - fibrin sealants, cell therapies and fistula plugs - have a lower risk of surgical sphincter damage/potential permanent incontinence but are associated with variable healing rates and greater recurrence than their surgical counterparts.

The BioHealx clinical data reported 0% incontinence, 0% device extrusion/migration, 59.4% (19/32) fistula complete healing at 12 months (N=32) with a further 31.2% (10/32) downgraded from transsphincteric fistula to either sinus or superficial fistula. For a subpopulation of the study (N=18), the clinical data further reported on long term durability of the BioHealx closure repair post 12 months follow up (N=18, 13 - 40 months, average 23.4 months). The recurrence rate at 12 months (N=32) and > 12-months (N=18) was 9.4% (3/32 clinical subjects).

There were 28 adverse events in total which were experienced across half (50%, 16/32 patients) of the study population. All adverse events were classified as either mild or moderate, with the exception of one serious adverse event (wound bleeding at the outer site of the partial fistulectomy - resolved), which resolved and was identified as unrelated to the study device.

There were no adverse events associated with sphincteric damage, incontinence, severe (FACES-WONG>4) persistent pain. nerve or vascular injury, device migration or extrusion. No events were unanticipated or occurred at a higher than anticipated frequency. The BioHealx safetv results demonstrated that the overall safety profile is acceptable and showed no unanticipated events.

The subject device provides uniform treatment of fistulas in ano eliminating user variability and simplifying the treatment of the condition by accurately identifying and closing the internal opening allowing healing by primary intention. In the Human factors study, which enrolled general and colorectal surgeons 50% of which were U.S. surgeons over 90% felt that the device was easy to use and provided a secure closure. A draining suture provides for drainage of the remaining fistula tract to the external opening. This has been shown to decrease the time required for surgical treatment of fistulas in ano.

Literature was used to provide comparator information; the literature had several limitations including poor quality OUS studies with variable definition of success. The BioHealx study was intended to recruit 35 patients and due to selection criteria only enrolled 32 patients for statistical analysis. Five subjects were noted to have protocol deviations (4 for BMI>35 and one for age >75) but were included in the study's statistical analysis. All thirty-two subjects have had 12 month follow up and 18 have had greater than 12 month follow up. The subject with the longest follow up is 40 months. These subjects all presented with recurrent transsphincteric fistulas and had undergone previous treatment. Subject meeting the primary and co-primary endpoints of complete and sustained healing of both the external opening without drainage at 12 months or longer follow up was 50 and 60% respectively. These results compared well with the literature comparator LIFT procedure which had a 12-month success rate in 9000 patients reported of 74% with a range of 40-94%. The 38 studies selected to evaluate the LIFT procedure were all OUS mostly Asian and of poor to moderate quality using the GRADE scoring system. However, of all the sphincter sparing procedures, the LIFT procedure most closely approximated the mechanism of action of the subject device and is the best comparator for evaluating the subject device. While the LIFT studies had variable definitions of success, most defined healing as complete closure of the external opening and no drainage.

23

The 32 patient BioHealx single arm pilot study reported no episodes of infection, device migration/ extrusion or incontinence and had a low recurrence rate of 9% all trans sphincteric. The LIFT studies report an average recurrence rate of 14% (30% intersphincteric and 70 % recurrent transsphincteric) with an incontinence rate of 9%. BioHealx appears to be safer than the LIFT procedure with a slightly lesser success rate at 12 or more months.

The probable risks of the subject device include recurrent or persistent fistula with perirectal abscess, incontinence of feces or flatus, device malfunction resulting in injury to the anal canal and surrounding musculature, foreign body sensation, sepsis, death, bleeding, etc. Recurrences requiring multiple repairs with multiple anesthetic risks is perhaps the most concerning. Only one episode of self-limited bleeding in a patient on Rivaroxaban who underwent a partial fistulotomy in addition to BioHealx placement, 7 minor post procedure infection and small abscesses, all self-limited and treated with antibiotic or local surgical drainage and a 9% recurrence rate were the only adverse events reported in the small multicenter single arm study submitted by the sponsor. The Instructions for Use has been revised instructing users that BioHealx should only be used in patients with cryptogenic, mature, simple transsphincteric, nonbranching fistulas. These are the only fistulas for which BioHealx was studied clinically.

The uncertainty around the benefits and risks of the subject device still exist due to the small study sample size of 32 patients. The pre- clinical porcine model poorly informs the safety and effectiveness of the subject device performance in humans. The safety of BioHealx appears to be better than the LIFT procedure comparator with a slightly less effectiveness in the treatment of fistulas in ano. The success rate is based on the most common definition of healing for both devices: closure of both the internal and external opening with no drainage. The sponsors offer a downgraded fistula as an added definition of healing which includes fistula healing with a persistent external opening with clear drainage. They have not substantiated this as healing of the entire fistula tract with imaging studies or exam under anesthesia. The sponsor described a "Flush" test performed in the clinic which showed no communication between the external and internal openings suggesting that the drainage was from a superficial fistula or sinus. However, this test was performed without rectal dilation, without anesthesia, and in most cases using Betadine alone as a flush without the propulsive force of gas forming hydrogen peroxide. These are important reasons to suspect a high false negative rate for the Flush test to demonstrate a communication between the internal and external fistula openings. Therefore, the most common definition of healing with closure of both the internal and external opening without drainage as the definition of success, which is the definition used by the majority of the OUS LIFT studies, will be considered successful fistula healing. In the Human Factors Study reported over 90% of participants felt that the device was easy to use, provided good visualization of the internal opening and securely closed the opening. 88% felt they would use the device to treat fistulas in ano, 6% felt they would use it selectively and 6% would use it only in a clinical study.

While the 12-month data show complete healing of both the internal and external opening without drainage in 59% of subjects, 41% failed to achieve healing leaving this subgroup of patients at risk of recurrent perirectal abscess with perineal sepsis which can lead to anal sphincter damage with incontinence, need for reoperation, Fournier's gangrene, systemic sepsis and even death in patients with sigmificant comorbidities such as diabetes. Post market actions which can mitigate the uncertainty regarding the safety and effectiveness of BioHealx may include:

24

1. A new, separate postmarket study to demonstrate the durability of BioHealx treatment of cryptogenic fistulas in ano including patients with the same inclusion and exclusion criteria as studied in the premarket study for at least 3 years that includes US patients and US general and colorectal surgeons.
  The benefit-risk analysis supports that the BioHealx- implant procedure for the BioHealx device is straightforward and delivery depth/position is controlled via the delivery system. The surgical procedure time is short for implantation of the BioHealx, with limited/no impact to existing anesthesia time, short hospital stays and no impact on medications use. A Postmarket Study will be conducted to further characterize benefit-risk due to the limitations of the small study size and uncertainty of generalizability of device performance in a patient population representative of the na.

The BioHealx Anal Fistula Device is intended for repair of soft tissue defects via tissue apposition. It is indicated for closure of the internal opening of mature, cryptogenic, transsphincteric, non-branching fistulas in ano via tissue apposition.

The risks of the BioHealx's technology and clinical study limitations are mitigated by the special controls, labeling, and post market study. Based on the totality of evidence and data with proposed mitigations of the BioHealx device, the probable risks are outweighed by the probable benefits.

Patient Perspectives

Patient feedback was additionally provided (72.2%, 13/18) at the post 12-month follow up visit via a study specific patient questionnaire. Prior to treatment with BioHealx, of the clinical study population, 53.8% (7/13) had endured their anal fistula for 1-8 (mean 3.17) years, the remainder for ≤ 6 months. 58.3% (7/12) listed discomfort and/or pain as affecting their life, 33.3% (4/12) indicated that discharge affected their life. Note: Not all respondents answered all questions.

Patient perspective data, post treatment with BioHealx, were obtained from self-reported quality of life (Fecal Incontinence Qualify of Life. SF-36 Qualify of Life) and pain scores (FACES-WONG) in the clinical study. There were no reports of incontinence or sphincter damage in the study. There were improvements in the Fecal Incontinence Quality of Life (FIQL) scores from baseline to 12-month visit across all four components (lifestyle, coping behaviour, depression/self-perception and embarrassment) that ranged from 7.2% - 11.6% improvement when compared to baseline. There was a 71% reduction in mean pain score (10-point Wong-Baker FACES®) from baseline to the last visit.

Benefit/Risk Conclusion

In conclusion, given the available information above, the data support that for the following intended use statement:

25

The Signum Surgical BioHealx Anal Fistula Device is indicated for closure of the internal opening of mature, cryptogenic, transsphincteric, non-branching fistulas in ano via tissue apposition.

The probable benefits outweigh the probable risks for the BioHealx Anal Fistula Device. The device provides benefits and the risks can be mitigated by the use of general controls and the identified special controls.

CONCLUSION

The De Novo request for the BioHealx Anal Fistula Device is granted and the device is classified as follows:

Product Code: QML Device Type: Anal fistula closure device Regulation Number: 21 CFR 878.4835 Class: II