# Presentation: 026992

## 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.

**Notes:**
Good afternoon,
I’m Peter Hudson, the lead reviewer for this application.  I will present the first of 3 reviews by FDA staff on the preclinical, clinical and statistical information regarding the Onyx Liquid Embolic System.

## Preclinical reviewDevice 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)

**Notes:**
Onyx comes in 2 viscosities, Onyx 18 and Onyx 34.  The Onyx Liquid Embolization System contains 1 vial of Onyx 18 or 34, one vial of DMSO and 3-1 mL DMSO compatible syringes. The sponsor is marketing two viscosities – Onyx 18 and Onyx 34 for use in arteriovenous malformations in which the depth of penetration is important.  The formulations are designated 18 or 34 based upon their respective viscosities, i.e., 18 and 34 centistokes, respectively.

## 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®)

**Notes:**
Onyx is indicated for the presurgical embolization of brain arteriovenous malformations.
Although intended for use as a presurgical tool, not all AVM patients will go on to have surgical resection.  In this study, nine patients (6 n-BCA and 3 Onyx) either had a partial resection, radiosurgery, or no surgery.  In the Cordis Neurovascular clinical study of the use of the Trufill n-BCA liquid embolic agent, 5 patients did not go on to have their AVM completely surgically resected.

## Chemistry

- Onyx® LES
- EVOH: ethyl vinyl alcohol copolymer
- Tantalum
- DMSO: dimethyl sulfoxide

**Notes:**
Onyx is a mixture of ethylene vinyl alcohol copolymer (EVOH) dissolved in dimethyl sulfoxide (DMSO).  Micronized tantalum powder is suspended in the liquid polymer/DMSO mixture to provide fluoroscopic visualization. Ethylene vinyl alcohol copolymer (EVOH) is synthesized by polymerizing a mixture of ethylene gas and vinyl acetate.  The resulting ethyl vinyl acetate is treated in a basic pH environment with sodium hydroxide and methanol to hydrolyze the acetate from the polymeric chain resulting in ethyl vinyl alcohol.  Although the toxicology of parent chemical compounds does not necessarily predict final compound toxicity, polyethylene and poly vinyl alcohol have medical device histories that would indicate relative safety.  Tantalum is chemically inert being susceptible only to hydrofluoric acid.  DMSO is an aprotic, polar solvent whose toxicology has been widely studied and has been a focus of review in this application . 

## 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)

**Notes:**
The sponsor has provided biocompatibility data in accordance with standard recommendations for medical devices having permanent, blood contacting exposure.  The 8% formulation with tantalum was tested in the evaluations.  The device passed all of the tests.

## Biocompatibility - hemocompatibility

- Hemolysis
- Lee-White clotting time
- C3a Complement activation

**Notes:**
The sponsor conducted hemocompatibility evaluations of the precipitated and washed device instead of how the product will be used in the patient.  It passed the hemolysis assessment, was observed to increase the clotting time by 18% and also caused complement activation.

## DMSO toxicology

- LD50’s: 2.5 g-11 g/kg (cats, dogs, monkeys, rabbits, and rats)
- Can cause hemolysis
- Can be angiotoxic

**Notes:**
LD50’s after intravenous dosing reveals that DMSO causes toxicity in cats, dogs, monkeys, rabbits, and rats in the range of 2.5-11 g.Kg.  DMSO has been demonstrated to be hemolytic.  A number of animal studies noted hematuria and hemoglobinuria – specifically after intravenous adminstration.  However, intravenous administration of DMSO appears to be well tolerated at concentrations lower than 50%.  Higher concentrations, given repeatedly, injure the injected vessels causing fibrosis proportional to the concentration and number of injections.  Persistent damage to the blood vessel causes a narrowing of the lumen.  More information regarding DMSO angiotoxicity will be presented with the animal model evaluations. 

## 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) experience
- Average vol.: 1.57 mL (24.7 mg/kg)
- Largest single vol.: 8.36 mL (131 mg/kg)

**Notes:**
The average volume of DMSO used in this study to embolize an AVM was 0.77 mL or 12.1 mg/kg – which is a dose approximately 200 fold below the lower limit of DMSO toxicity reported on the previous slide.  Forty-three percent of the patients in this study had more than one embolization procedure.  In clinical experience to date, outside of the U.S., the average volume used was 1.57 mL or approximately 25 mg/kg or approximately 100 fold lower than toxicity values reported in lower animals.

## 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

**Notes:**
Animal studies have shown that if concentrated DMSO is given too quickly, severe vasospasm and angiotoxicity will occur.  In early evaluations of the embolic agent, Chaloupka et al studied the device in the swine rete mirabile. 
	severe vasospasm
	subarachnoid hemorrhage
	stroke
	histologically they saw
	endothelial cell denudation
	thrombosis
	transmural necrosis
	extravasation of the embolic agent
	Conclusion – DMSO angiotoxic
Additional studies have shown that if a low dose of DMSO is administered using a very slow injection rate, vasospasm and angiotoxicity is not observed.  Murayama et al., evaluated the embolic agent using  slow infusion in to reduce arterial damage caused by concentrated DMSO. 
	0.3 ml priming dose followed by a 0.5 	ml dose of DMSO slowly 	administered resulted in no vascular 	toxicities
Finally, in a study by Chaloupka to determine the rate and volume best tolerated for use in human embolization procedures, 0.5 mL and 0.8 mL quantities of DMSO were injected in the swine rete mirabile model. The results indicated that a slow and controlled infusion of DMSO (anhydrous) had no severe or permanent vascular effect in the swine model.  The dose rate of 0.5 mL/90 sec. (0.33 mL/min.) resulted in low vasospasm scores, low vasospasm duration times and no permanent vascular damage. 

## 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

**Notes:**
In this study the sponsor investigated the effectiveness and safety of Onyx in embolizing the swine rete mirabile.  The investigators used the rates and volumes of Onyx determined in previous studies to be safe in the embolization procedure.  3, 6 and 12 month follow-up with histopathologic assessments were conducted.  No vasospasm was observed.  A robust foreign body response was seen at 3 and 6 months.  No evidence of angionecrosis was seen however focal elastica disruption was seen in most tissues.  At 12 months the histological findings were equivalent to the 3 and 6 month findings however there was 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

**Notes:**
The purpose of the study was to evaluate the feasibility of treating intracranial aneurysms by embolization with the subject device.  The information obtained in this evaluation, although more directly applicable to treatment of aneurysms, can be extrapolated to the treatment of AVMs and the histopathologic assessment for tissue responses to the material. 	Experimental aneurysms created via the vein graft technique
	Staged embolizations were done using a balloon catheter positioned distal to the embolization site and allowing blood to flow in between embolizations Aneurysm histopathology specimens at 3, 6, and 12 month time periods showed complete healing of the aneurysm neck with acceptable tissue response comparable to GDC treated aneurysms with an inflammatory response diminishing at 12 months Healthy neointimal tissue remodeling was observed across the aneurysm neck in continuity with the parent artery lumen

## Human experienceOnyx® 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

**Notes:**
Human experience and evidence regarding Onyx and angio-biocompatibility is limited.
7 AVMs embolized with Onyx and then surgically excised were histologically assessed.
Time of treatment to surgical excision ranged from 3-19 months.
No evidence of vascular necrosis, rupture or extravasation of the Onyx material was found.
In addition, the sponsor obtained CT, MRI and flat film skull x-rays of patients embolized with nBCA or Onyx.
In both groups roughly half had findings indicating a change – preoperatively to postoperatively.
A core reader assessed the images to determine if they were device related.
The observations were determined to be due to radiosurgery, surgical resection and or the natural history of the AVM and not due to the device.
An FDA radiologist reviewed the images and determined that the reader’s interpretation was consistent with the data.

## DMSO potential vascular toxicity and concern with repeat injection

- Rate
- Repetition
- DMSO volumes
- Number of procedures
- Indicated as a presurgical tool

**Notes:**
We know that the rate of infusion of DMSO can seriously influence whether angiotoxicities occur.  Chaloupka et al. demonstrated that rapid infusion of DMSO in the swine rete mirabile model caused severe vasospasm, stroke, endothelium denudation and transmural necrosis. In further studies, a slow infusion of the embolic agent resulted in limited vasospasm duration and no permanent vascular damage.  Some investigators have found that repeated intravenous injections of undiluted DMSO were damaging to the veins of dogs and rats.  In the dog study the toxicity was observed with injections of 300 mg/kg/day during a 6 day/week, 4 week schedule.  The average dose of DMSO injected per embolization procedure in this clinical study was 0.77 mL or 12.1 mg/kg.  This amount is 200 fold lower than the low end of LD50’s observed in animals receiving intravenous injections of DMSO.  Embolization of AVMs sometimes requires multiple, staged procedures.  In this clinical study 43.5% of the patients had 2 or more procedures.  In the sponsor’s reported worldwide clinical experience approximately 30% of patients will receive more than one embolization procedure.  The embolization procedures are typically spread out over a period of time.  The device is indicated for the presurgical embolization of AVMs.  In this study 9 patients did not go on to have complete surgical resection of their AVM.

## Additional preclinical testing

- Effect of radiation on polymer
- Interaction of DMSO with platinum coils
- Interaction of DMSO and Cyanoacrylate

**Notes:**
MTI has conducted additional testing to determine if the polymer may chemically degrade due to irradiation or whether the DMSO solvent might interact with other embolic agents used in the treatment of AVMs.  Chemical analyses of the polymer after having been irradiated indicated no discernible changes.  Similarly, HPLC analyses of DMSO incubated with platinum coils or with Histocryl found no evidence of a chemical interaction.

## Conclusions

- Extensive biocompatibility assessments performed
- Animal evaluations indicate relative safety
- DMSO repeat injection concern

**Notes:**
Onyx has been demonstrated through standard testing to be biocompatible.  The tantalum and EVOH chemical components are relatively non-toxic entities.  The angiotoxic effect of DMSO has been investigated.  Controlled, slow infusion of the DMSO/EVOH and tantalum mixture was demonstrated to limit the extent and duration of vasospasm.  The device is effective in animal embolization model evaluations – swine rete and swine aneurysm comments.  Histologic examinations at 12 months in both a swine rete mirabile and a swine carotid artery/vein graft aneurysm model indicated that the inflammatory response to the material was equivalent to other legally marketed embolization agents.  Clinical articles discussing the response to PVA particles and to cyanoacrylate glue embolization agents note the incidence of angionecrosis, the presence of foreign body giant cells, and perivascular cuffing by mononuclear inflammatory cells.  The sponsor has a well-thought out training program for physicians that alerts new users of the concerns related to DMSO and vascular toxicity, and provides them with in vitro and in vivo hands-on opportunity for device familiarlization. 

## 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 |

## Patient Demographics (n=102)

| 
Demographics | n-BCA
n=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) |
| Gender
Male
Female | 
48.2% (27/56)
51.7% (26/56) | 
43.5% (20/46)
56.5% (26/46) |
| BMI
Mean +/- SD (n)
Median (range) | 
24.4 + 4.6 (53)
23.6 (15.1-37.2) | 
28.1 + 6.3 (39) p<0.05
27.4 (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) |

## Medical History (n=102)

|   | n-BCA
n=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)**

## Primary Presenting Symptoms (n=102)

|  | n-BCA
n=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)**

## Pretreament Assessment (n=103 AVMs in 102 pts)

|  | n-BCA
n=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)**

## Pretreament Assessment -  cont.(n=103 AVMs in 102 pts)

| Spetzler-Martin Grade | n-BCA
n=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)**

## Pretreament Assessment -  cont. n=103 AVMs in 102 pts)

|  | n-BCA
n=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® Usage Details

|   |  | 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-BCA Usage Details

|   | n-BCA
n=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**

##      Device Usage

| Number Embolization Procedures | n-BCA
n=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**

## Coil Usage

|  | n-BCA
n=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**

## Percentage of Patients with > 50% Exclusion of AVM

|   | 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**

## Blood Loss Index

|   | n-BCA
n=44 | Onyx®
n=43 |
| --- | --- | --- |
| Mean+SD | 892 +1067 | 1127 +1401 |
| Median | 475 | 550 |
| Range | 100 - 5000 | 50 - 6550 |

**Blood Loss Index**

## Surgical Resection Time (min)

|   | n-BCA
n=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)**

## Neurological Assessment

| NIH Score Change from Baseline | Status | Change Post-Embolization |  | Change Post-Surgery |  |
| --- | --- | --- | --- | --- | --- |
|  |  | n-BCA
n=49 | Onyx®
n=43 | n-BCA
n=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**

## Neurological Assessment (cont.)

| Barthel Score Change from Baseline | Status | Change Post-Embolization |  | Change Post-Surgery |  |
| --- | --- | --- | --- | --- | --- |
|  |  | n-BCA
n=50 | Onyx®
n=43 | n-BCA
n=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.)**

## Neurological Assessment (cont.)

| Presenting with normal Glasgow Coma Scale (=15) |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
| GOS | Post-Embolization |  |  | Post-Surgery |  |
|  | n-BCA
n=46 | Onyx®
n=40 |  | n-BCA
n=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.)**

## 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.)**

## Physician Ratings of Device Performance

|  | 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**

## Frequency of Complications – Cranial

| 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 – Cranial

| Complications | 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%) |

## Frequency of Complications – non-cranial

| 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 Endpoints

|  | n-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 #1Onyx® 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 #2Onyx® 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 #3Onyx® 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 #4Onyx® 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 #5Onyx® 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?