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Micro Therapeutics, Inc.Onyx® Liquid Embolic System (Onyx® LES)
Neurological Devices Panel Meeting August 5, 2003 FDA presenters
Preclinical Peter L. Hudson, Ph.D.Clinical Ann H. Costello, Ph.D., D.M.D.Statistical Judy S. Chen, M.S.
Preclinical reviewDevice description - Onyx ® LES
Onyx® Liquid Embolic System (LES) one vial (1.5 mL) of Onyx ® (18 or 34)
Onyx 18 = 6% EVOH, Onyx 34 = 8% EVOH
[EVOH = ethyl vinyl alcohol copolymer]
one vial of DMSO (1.5 mL)[DMSO = dimethyl sulfoxide]
3 DMSO compatible syringes (1 mL)
Indication for use
IFU: presurgical embolization of brain arteriovenous malformations
Not all patients ended up being surgically resected in this study (6 n-BCA, 3 Onyx®)
Chemistry
Onyx® LES
EVOH: ethyl vinyl alcohol copolymerTantalumDMSO: dimethyl sulfoxide
Biocompatibility
Cytotoxicity Sensitization Irritation Acute systemic toxicity Implantation (7, 30, 90, 180, 360 days) Gentoxicity/mutagenicity (Ames, Chromosomal
Aberration, Mouse micronucleus) Carcinogenicity (rasH2 Transgenic mouse)
Biocompatibility - hemocompatibility
Hemolysis
Lee-White clotting time
C3a Complement activation
DMSO toxicology
LD50’s: 2.5 g-11 g/kg (cats, dogs, monkeys, rabbits, and rats)
Can cause hemolysis
Can be angiotoxic
DMSO dose
Average vol. = 0.77 mL of DMSO (0.27 mL catheter plus 0.5 mL Onyx®) = 12.1 mg/kg
43.5% of the patients received more than 1 Onyx® embolization procedure
Outside US (OUS) experienceAverage vol.: 1.57 mL (24.7 mg/kg)Largest single vol.: 8.36 mL (131 mg/kg)
DMSO Angiotoxicity in animal models
Chaloupka et al., Technical feasibility and histopathologic studies of ethylene vinyl copolymer using a swine endovascular embolization model, Am J Neuroradiol, 1994
Murayama et al., Nonadhesive liquid embolic agent for cerebral arteriovenous malformations: preliminary histopathological studies in swine rete mirabile, Neurosurg, 1998
Swine rete mirabile model
Embolization procedure included the use of rate and volumes as evaluated in previous studies
3, 6, 12 month follow-up with histopathology No vasospasm observed Robust foreign body response No arterial angionecrosis 12 month histology indicated a decrease in chronic
inflammation
Aneurysm model – histopathologic comparison to GDC coils Aneurysms surgically created on carotid artery
using vein graft technique
3, 6, 12 month follow-up with histopathology
Tissue response to Onyx® judged equivalent to GDC coils
Human experienceOnyx® angio-biocompatibility Histopathologic examination of 7 AVMs
embolized with Onyx® – 6/7 had more than 1 embolization
MRI/CT evaluation of AVMs treated with Onyx® or n-BCA
DMSO potential vascular toxicity and concern with repeat injection Rate Repetition DMSO volumes Number of procedures Indicated as a presurgical tool
Additional preclinical testing
Effect of radiation on polymer
Interaction of DMSO with platinum coils
Interaction of DMSO and Cyanoacrylate
Conclusions
Extensive biocompatibility assessments performed
Animal evaluations indicate relative safetyDMSO repeat injection concern
Clinical review
Ann H. Costello, Ph.D., D.M.D.
Indications for Use
The Onyx® Liquid Embolization System is an artificial embolization device intended for use in the treatment of brain arteriovenous malformations, when embolization is indicated to minimize blood loss to reduce the BAVM size prior to surgery.
Objective
Demonstrate that Onyx® was no worse than n-BCA in terms of efficacy within a 20% specified clinical tolerance.
Patient Inclusion Criteria BAVM in cerebral cortex, cerebellum, or dura
mater. BAVM with Spetzler Martin grade of I, II, III, or
IV. If BAVM has a Spetzler Martin grade of I or II,
the anticipated benefit of embolization for surgical resection is greater than the risk of the embolization procedure.
Patient Accountability
n-BCA Onyx®
# Pts randomized 57 51
Protocol violation Dural fistulae patients
1 5
# Pts for Treatment 56 46
Late Screening Failure 2 0
Complete surgical resection 45 41
Partial resection or radiosurgery 6 3
Pts ongoing 1 2
Pts lost to follow-up 2 0
Demographicsn-BCAn=56
Onyx®N=46
Age (yrs)Mean +/- SD (n)Median (range)
35.1 + 14.3 (56)36.0 (10.0-66.0)
40.3 + 16.3 (46)42.5 (7.0-72.0)
GenderMaleFemale
48.2% (27/56)51.7% (26/56)
43.5% (20/46)56.5% (26/46)
BMIMean +/- SD (n)Median (range)
24.4 + 4.6 (53)23.6 (15.1-37.2)
28.1 + 6.3 (39) p<0.0527.4 (16.7-45.0)
Systolic Blood Pressure (mmHg)Mean +/- SD (n)Median (range)
123 + 14 (56)120 (80-171)
126 + 16 (46)123 (98-167)
Diastolic Blood Pressure (mmHg)Mean +/- SD (n)Median (range)
70 + 10 (56)70 (50-90)
71 + 12 (46)70 (48-98)
Patient Demographics (n=102)
n-BCAn=56
Onyx®n=46
CAD 1.8% (1/56) 6.5% (3/46)
HTN 19.6% (11/56) 17.4% (8/46)
Diabetes 5.4% (3/56) 4.3% (2/46)
Neuro History
Seizure 19.6% (11/56) 10.9% (5/46)
Stroke 0.0% (0/56) 2.2% (1/46)
Aneurysm *8.9% (5/56) 0.0% (0/46)
Other AVM 3.6% (2/56) 0.0% (0/46)
Intracranial Hemorrhage (>1 yr)
11% (6/56) 6.5% (3/46)
Neuro Interventions
Surgery (Clipping) 5.4% (3/56) 0.0% (0/46)
*p<0.05
Medical History (n=102)
n-BCAn=56
Onyx®n=46
Acute Bleed (<30 days)
14.3% (8/56) 15.2% (7/46)
Remote Bleed (>30 days<1 year)
17.9% (10/56) 19.6% (9/46)
Neurologic Deficits 51.8% (29/56) 39.1% (18/46)
Neurologic Symptoms 14.3% (8/56) 19.6% (9/46)
None 1.8% (1/56) 6.5% (3/46)
Primary Presenting Symptoms (n=102)
n-BCAn=57 AVMs in 56 patients
Onyx®n=46 AVMs in 46 patients
AVM Location
Right 55.4% (31/56) 63.0% (29/46)
Left 41.1% (23/56) 34.8% (16/46)
Midline 3.6% (2/56) 2.2% (1/46)
AVM in eloquent area of brain
48.2% (27/56) 45.7% (21/46)
Venous Drainage
Deep 8.9% (5/56) 15.2% (7/46)
Superficial 62.5% (35/56) 63.0% (29/46)
Both 28.6% (16/56) 21.7% (10/46)
Pretreament Assessment (n=103 AVMs in 102 pts)
Spetzler-Martin Grade n-BCAn=57 AVMs in 56 patients
Onyx®n=46 AVMs in 46 patients
I 25.0% (14/56) 10.9% (5/46)
II 25.0% (14/56) 43.5% (20/46)
III 30.4% (17/56) 26.1% (12/46)
IV 19.6% (11/56) 19.6% (9/46)
AVM Size (Core Lab, mm3)
Mean+SD 16.0 +20.0 26.3 +45.2
Median 8.1 13.6
Range 0.08 - 94.9 0.17 - 290.5
Pretreament Assessment - cont.(n=103 AVMs in 102 pts)
n-BCAn=56
Onyx®n=46
Glasgow Coma Score
0-6 3.6% (2/55) 2.2% (1/46)
7-14 3.6% (2/55) 8.7% (4/46)
>14 92.7% (51/54) 89.1% (41/46)
Barthel Index
0-25 3.7% (2/54) 8.7% (4/46)
26-75 1.9% (1/54) 4.3% (2/46)
76-100 94.4% (51/54) 87.0% (40/46)
NIH Stroke Scale
0 75.5% (40/53) 60.9% (28/46)
1-4 18.9% (10/53) 30.4% (14/46)
5-10 5.7% (3/53) 2.2% (1/46)
>10 0.0% (0/53) 6.5% (3/46)
Pretreament Assessment - cont. n=103 AVMs in 102 pts)
Onyx® (n=46)
Microcatheter Use (202 catheters) FlowRider 22
Ultraflow 151
Rebar 17
MTI Unknown 12
Initial Catheter Position (n=183 Injections)
Wedged 36
Unwedged 144
Missing 3
Onyx® Formulation Used Onyx®-18 Alone 55/72 (76%)
Onyx®-34 Alone 9/72 (13%)
Onyx®-18 and 34 8/72 (11%)
Injection Parameters No Agent Delivered 10 Procedures
Mean Vol Injection 0.50 ml
Mean Duration Injection 5.44 min
DMSO Usage Mean vol DMSO Injected 0.27 ml
Mean DMSO Injection Time 90.9 sec
Onyx® Usage Details
n-BCAn=54
Oil:n-BCA Ratio
Within Guidelines (3:1-1:2)
71%
Higher Concentration Oil
23%
Higher Concentration n-BCA
6%
No Agent Delivered 8 Procedures
Mean Vol n-BCA Delivered
0.38 ml
n-BCA Usage Details
Number Embolization Procedures
n-BCAn=54
Onyx ®n=46
# Pts % Pts # Pts % Pts
1 34 63.0% 26 56.5%
2 9 16.7% 11 23.9%
3 7 13.0% 6 13.0%
4 2 3.7% 1 2.2%
5 2 3.7% 1 2.2%
6 0 0.0% 0 0.0%
7 0 0.0% 1 2.2%
Total # Pts 54 100% 46 100%
Total Procedures 91 82
Avg # Procedures/Pt(min, max)
1.7(1,5)
1.8(1,7)
Device Usage
n-BCAn=54
Onyx®n=46
# Procedures in which Coils were used as adjunct 23/91 (25.3%) 8/82* (9.8%)
Reason for Coil Usage
High Flow Fistula 20 4
Other 3 4
Type of Coils Used+
GDC 2 4
Straight Fiber Coil 1 2
3D 0 1
Liquid Coils 20 4
*p=0.008
Coil Usage
Endpoints
Primary: 50% or greater angiographic reduction in AVM size by core laboratory was required for success.
Secondary: Surgical blood loss
Surgical resection time
n-BCA Onyx® Difference
[95% C.I.]Relative Risk
Primary Efficacy by Core Lab
84.3% (43/51)
97.6%(41/42)
13.3%[2.3%, 24.3%]
1.16[1.01, 1.32]
Percentage of Patients with > 50% Exclusion of AVM
p=0.55
n-BCAn=44
Onyx®n=43
Mean+SD 892 +1067 1127 +1401
Median 475 550
Range 100 - 5000 50 - 6550
Blood Loss Index
n-BCAn=42
Onyx®n=42
Mean +SD 411 +201 399 +179
Median 344 366
Range 150 - 1019 82 - 940
p=0.99
Surgical Resection Time (min)
NIH Score Change from Baseline
Status Change Post-Embolization Change Post-Surgery
n-BCAn=49
Onyx®n=43
n-BCAn=38
Onyx®n=39
<0 Declined 10.2% (5/49)
11.6% (5/43)
36.8% (14/38)
28.2% (11/39)
0 Unchanged 71.4% (35/49)
72.1% (31/43)
52.6% (20/38)
59.0% (23/39)
1-5 Improved 18.3% (9/49)
14.0% (6/43)
10.5% (4/38)
10.3% (4/39)
>5 Improved 0% (0/49)
2.3% (1/43)
0% (0/38)
2.6% (1/39)
Neurological Assessment
Barthel Score Change from Baseline
Status Change Post-Embolization Change Post-Surgery
n-BCAn=50
Onyx®n=43
n-BCAn=40
Onyx®n=38
<0 Improved 2% (1/50)
0% (0/43)
5.0% (2/40)
0% (0/38)
0 Unchanged 68.0% (34/50)
72.1% (31/43)
50.0% (20/40)
52.6% (20/38)
5-10 Declined 12.0% (6/50)
4.7% (2/43)
5.0% (2/40)
7.9% (3/38)
15-50 Declined 12.0% (6/50)
16.3% (7/43)
12.5% (5/40)
15.8% (6/38)
51-100 Declined 6.0% (3/50)
7.0% (3/43)
27.5% (11/40)
23.7% (9/38)
Neurological Assessment (cont.)
Presenting with normal Glasgow Coma Scale (=15)
GOS Post-Embolization Post-Surgery
n-BCAn=46
Onyx®n=40
n-BCAn=36
Onyx®n=34
0 80.4% (37/46) 67.5% (27/40) 66.7% (24/36) 47.1% (16/34)
I 17.4% (8/46) 22.5% (9/40) 11.1% (4/36) 23.5% (8/34)
II 0% (0/46) 7.5% (3/40) 5.5% (2/36) 17.6% (6/34)
III 2.2% (1/46) 2.5% (1/40) 11.1% (4/36) 11.8% (4/34)
IV 0% (0/46) 0% (0/40) 2.8% (24/36) 0% (0/34)
V 0% (0/46) 0% (0/40) 0% (0/36) 0% (0/34)
Neurological Assessment (cont.)
Presenting with Glasgow Coma Scale with Some Deficits (<15)
GOS Post-Embolization Post-Surgery
n-BCA n=3
Onyx® n=3
n-BCA n=3
Onyx® n=3
0 0% (0/3) 0% (0/3) 0% (0/3) 0% (0/3)
I 33.3% (1/3) 33.3% (1/3) 33.3% (1/3) 33.3% (1/3)
II 0% (0/3) 0% (0/3) 0% (0/3) 0% (0/3)
III 66.7% (2/3) 66.7% (2/3) 66.7% (2/3) 66.7% (2/3)
IV 0% (0/3) 0% (0/3) 0% (0/3) 0% (0/3)
V 0% (0/3) 0% (0/3) 0% (0/3) 0% (0/3)
Neurological Assessment (cont.)
n-BCA(n=54, 85 embolizations)
Onyx®(n=46, 75 embolizations)
Rating Performance Rating Performance
Attribute Poor Unsatisfactory Acceptable Good Excellent Poor Unsatisfactory Acceptable Good Excellent
Control-lability 3.5%(3/85)
5.9% (5/85)
45.9%(39/85)
27.0%(23/85)
17.7%(15/85)
1.3%(1/75)
0% 6.7% (5/75)
38.7%(29/75)
53.3%(40/75)
Visualization 0% 0% 13.0% (11/85)
38.8%(33/85)
48.2% (41/85)
5.4%(4/75)
12.0% (9/75)
37.3% (28/75)
24.0%(18/75)
21.3%(16/75)
Penetration 3.5%(3/85)
17.7% (15/85)
38.8% (33/85)
21.2%(18/85)
18.8% (16/85)
2.7%(2/75)
0% 28.0% (21/75)
45.3%(34/75)
24.0%(18/75)
Total # of patients with >1 Emboliz.
19 20
Total # of Embolizations
89 79
Physician Ratings of Device Performance
Complications Onyx® (n=46) n-BCA (n=54)
# of events # of patients(% of patients)
# of events # of patients(% of patients)
Headache +/- nausea and vomiting 32 22 (47.8%) 32 25 (46.3%)
Worsening neuro status Persistent Transient
31 15 16
25 (54.3%) 11 (23.9%) 14 (30.4%)
39 17 22
33 (61.1%)(15) (27.8%)(18) (33.3%)
Delivery catheter removal difficulty 10 7 (15.2%) 0 0
Intracranial hemorrhage 9 8 (17.4%) 10 9 (16.7%)
Poor penetration/visualization 5 4 (8.7%) 0 0
Hydrocephalus 4 4 (8.7%) 1 1 (1.9%)
Laboratory imaging abnormality 3 1 (2.2%) 8 7 (13.0%)
Failed access 3 3 (6.5%) 5 5 (9.3%)
Vasospasm 3 1 (2.2%) 4 3 (5.6%)
Infection 2 2 (4.3%) 0 0
Frequency of Complications – Cranial
Complications – Cranial (cont.)Death 2 2 (4.3%) 0 0
Stroke 2 2 (4.3%) 0 0
Catheter shaft rupture 2 2 (4.3%) 0 0
Vessel dissection/perforation 1 1 (2.2%) 3 3 (5.6%)
Embolization of unintended vessel 1 1 (2.2%) 3 3 (5.6%)
Seizure 1 1 (2.2%) 1 1 (1.9%)
Catabolic status 1 1 (2.2%) 1 1 (1.9%)
Fragmentation of Onyx® 1 1 (2.2%) 0 0
Small amount of Onyx® in vein 1 1 (2.2%) 0 0
Prolonged polymerization time 0 0 3 3 (5.6%)
Cerebral vessel perfusion 0 0 1 1 (1.9%)
Delayed polymerization 0 0 1 1 (1.9%)
Premature polymerization 0 0 1 1 (1.9%)
High flow fistula 0 0 1 1 (1.9%)
Total Number of events 114 114
Complications Onyx® (n=46) n-BCA (n=54)
Frequency of Complications – CranialComplications Onyx (n=46) n-BCA (n=54)
FDA MTI FDA MTI
Headache +/- nausea and vomiting
37 (80.4%) 22 (47.8%) 39 (72.2%) 25 (46.3%)
Worsening neuro status Persistent Transient
36 (78.3%)27 (58.7%)9 (19.6%)
25 (54.3%) 11 (23.9%) 14 (30.4%)
39 (72.2%)23 (42.6%)16 (29.6%)
33 (61.1%) 15 (27.8%) 18 (33.3%)
Intracranial hemorrhage 9 (19.6%) 8 (17.4%) 9 (16.7%) 9 (16.7%)
Seizures 2 (4.3%) 1 (2.2%) 2 (3.7%) 1 (1.9%)
Vasospasm 3 (6.5%) 1 (2.2%) 3 (5.5%) 3 (5.6%)
Complications Onyx® (n=46) n-BCA (n=54)
# of events # of patients (% of patients)
# of events # of patients(% of patients)
Patient discomfort 17 13 (28.3%) 11 11 (20.4%)
Infection 6 6 (13.0%) 5 5 (9.3%)
Access site bleeding 5 2 (4.3%) 0 0
Medication reaction 4 3 (6.5%) 3 3 (5.6%)
Fever 3 3 (6.5%) 2 2 (3.7%)
Multi-organ system complication 2 1 (2.2%) 2 2 (3.7%)
Respiratory failure 2 2 (4.3%) 1 1 (1.9%)
Cardiac arrhythmia 1 1 (2.2%) 1 1 (1.9%)
Headache +/- nausea and vomiting
1 1 (2.2%) 0 0
Tongue swelling 1 1 (2.2%) 0 0
Psychotic episode 1 1 (2.2%) 0 0
Hypertension 1 1 (2.2%) 0 0
Severe bleeding/Low Hct requiring transfusion
0 0 2 2 (3.7%)
Limb ischemia 0 0 1 1 (1.9%)
Thrombocytopenia 0 0 1 1 (1.9%)
Total Number of Events 44 29
Frequency of Complications – non-cranial
SUMMARY Effectiveness:
Onyx® and n-BCA are equivalent in attaining a ≥ 50% reduction in the AVMs.
Safety: - 2 patients died and 2 had strokes in the Onyx® group.- More patients in the Onyx® group had hydrocephalus, reported discomfort and had access site bleeding.- There were 10 reports of delivery catheter removal difficulty in the Onyx® group similarly there were more reports of poor penetration/visualization Onyx® group.
Statistical Comments for Onyx® Liquid Embolic System
Judy Chen, M. S.
OSB/DBS
Study Design
Randomized parallel group trial of 17 centers and 108 patients. All patients were diagnosed with brain arteriovenous malformations.
Primary effectiveness endpoint : Proportion of patients who are rated as “success”
Secondary effectiveness endpoints:
Surgery blood loss
Surgical resection time
Study Objective
To demonstrate that the proportion of patients who are “successes” in Onyx® group is not inferior to that in the n-BCA control group.
Inferior : the success proportion in control group is higher than that in the experimental Onyx® group by at least 20%.
Analyses Populations
FDA’s ITT (n=108) ---All 108 randomized patients Sponsor’s ”ITT” (n=93) ---2 late screen failures, 6 dural
fistulae, 4 films not analyzable and 3 ongoing were excluded from all randomized patients.
Sponsor’s ”conservative ITT” (n=96)---Adding 2 ongoing in the Onyx® group (counted as failures) and 1 in the control group (counted as success) to the above “ITT” population
Sponsor’s “ITT” Population (n=93) Investigator n-BCA
(success/total)Onyx® (success/total)
Barnwell 5/6 4/4
Berenstein 3/3 2/2
Rasmussen 3/3 4/4
Pryor 6/7 5/6
Watson 2/6 4/4
Rosenwasser 1/1 2/2
Purdy 3/3 4/4
Malisch 1/1 1/1
-------continue------Sponsor’s “ITT” Population (n=93)Sanders 1/2 2/2
Mericle 4/4 2/2
Duckweiler 2/2 2/2
Mawad 4/4 2/2
DeNardo 5/5 4/4
Marks 2/2 0
McDougall 0 1/1
Dion 0/1 0
Rodriguez-Mercado
1/1 2/2
Sponsor’s “ITT” Result (n=93)
Summing total numbers of patients and number of successes over 17 centers, and excluding patients who were late screen failures (n=2), patients with dural fistulas (n=6) and patients with films not analyzable or patients who are ongoing (3 in the control n-BCA group and 4 in Onyx® group), proportions of successes are 84% in the control group and 98% in the Onyx® group.
The treatment difference (14%) is statistically significant with 2-sided 95% confidence interval (2.3, 24.3%).
Sponsor’s ”conservative ITT” Results (n=96) Summing total numbers of patients and number of
successes over 17 centers, and assuming patients who are ongoing as failures(2) in the Onyx® group and successes (1) in the control group, proportions of successes are 84.6% in the control group and 93.2% in the Onyx® group.
The treatment difference is 8.6% with 2-sided 95% confidence interval (-3.8%, 20.9%), which is higher than the pre-specified -20% tolerable difference.
Comments for sponsor’s “ITT” analyses
Original Randomization is not preserved.
The “center” or stratification is ignored.
FDA’s ITT (All Randomized) (n=108)Investigator n-BCA
(success/total)Onyx® (success/total)
Barnwell 5/6 4/6
Berenstein 3/3 2/3
Rasmussen 3/4 4/4
Pryor 6/7 5/6
Watson 2/7 5/7
Rosenwasser 1/2 2/2
Purdy 3/5 4/4
Malisch 1/1 1/2
-------continue------All Randomized (n=108)Sanders 1/2 2/2
Mericle 4/5 2/4
Duckweiler 2/2 2/2
Mawad 4/4 2/2
DeNardo 5/5 4/4
Marks 2/2 0
McDougall 0 1/1
Dion 0/1 0
Rodriguez-Mercado
1/1 2/2
All Randomized (n=108)Odds Ratio Odds Ratio : the ratio of the odds of being a success
versus being a failure in the Onyx® group to the odds in the control n-BCA group. An odds ratio of 1 indicates the treatment effects are equal.
Homogeneity of Odds Ratio is not statistically rejected (p=0.46).
Common Odds Ratio estimate:1.55 with 1-sided 95% lower limit 0.68.
All Randomized (n=108)Difference Homogeneity across investigators is assumed. The MH (Mantel-Haenszel) treatment difference
is 6.6 % with 1-sided 95% lower confidence limit -7.2%, which is higher than the pre-specified tolerable difference of -20%.
Secondary Endpointsn-BCA Onyx®
Blood Loss Index n=44 n=43
Mean (s. d.) 892 (1067) 1127 (1401)
Median 475 550
Resection Time n=42 n=42
Mean (s. d.) 411 (202) 399 (179)
Median 344 366
Conclusions
Comparing Onyx® to control n-BCA, the odds ratio for “success” is 1.55, with 1-sided 95% confidence limit 0.68.
Assuming homogeneity of treatment difference across centers, Onyx® is not inferior to control n-BCA in proportion of patients rated as successes. .
No statistical conclusion can be reached on blood loss or resection time.
Panel Questions
FDA has questions that will be posed to the panel for their comment and opinion. These questions concern:
DMSO/Onyx® repeat injection Clinical safety evaluation Clinical effectiveness evaluation Physician training Long term implantation and follow-up
The questions will be presented after panel presentation and discussion of the application.
Panel Question #1Onyx® Liquid Embolic System Preclinical animal evaluations included in this PMA have
shown that the rate of infusion of DMSO can cause vasospasm and vascular wall damage. Patients undergoing staged embolization procedures for cerebral AVMs will be exposed repeatedly to DMSO prior to resection.
Do you believe that the data in the PMA adequately support the safety of repeated exposure to DMSO? If not, please provide suggestions on the additional preclinical studies that you believe are needed to demonstrate the safety of the repeated exposure to DMSO.
Panel Question #2Onyx® Liquid Embolic System
21 CFR 860.7(d)(1) states that there is a reasonable assurance that a device is safe when it can be determined that the probable benefits to health from use of the device for its intended uses, when accompanied by adequate instructions for use and warnings against unsafe use, outweigh any probable risks.
Please discuss whether the data in the PMA provide a reasonable assurance of safety.
Panel Question #3Onyx® Liquid Embolic System 21 CFR 860.7(e)(1) states that there is a reasonable
assurance that a device is effective when it can be determined, based upon valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warning against unsafe use, will provide clinically significant results.
Please discuss whether the data in the PMA provide a reasonable assurance of effectiveness.
Panel Question #4Onyx® Liquid Embolic System A number of complications were observed in the study that
appear to relate to user training. Of particular concern were three device-related complications: difficulty in removing the catheter (10 – Onyx®, 0 – n-BCA), catheter shaft rupture (2 – Onyx®, 0 – n-BCA) and poor penetration/visualization (5 – Onyx®, 0 – n-BCA).
Please comment on the sponsor’s proposed training plan and whether you believe it is adequate to help ensure proper device use.
Panel Question #5Onyx® Liquid Embolic System The device is intended for presurgical embolization and,
therefore, the material is meant to be removed during surgical resection of the AVM. Although patients were enrolled in this study based upon the criterion that they were surgical candidates, in some cases the clinical course of treatment changed such that some patients did not undergo surgical excision, post-embolization.
Considering that it is probable that this scenario will also arise under clinical use, if you recommend approval, do you believe a long-term follow-up study for patients not undergoing surgical resection of their AVM should be conducted as a condition of approval?
