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Micro Therapeutics, Inc. Onyx Liquid Embolic System Onyx LES

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Device description - Onyx LES. Onyx Liquid Embolic System (LES) ... Onyx LES. EVOH: ethyl vinyl alcohol copolymer. Tantalum. DMSO: dimethyl sulfoxide ... – PowerPoint PPT presentation

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Title: Micro Therapeutics, Inc. Onyx Liquid Embolic System Onyx LES


1
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.

2
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)

3
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)

4
Chemistry
  • Onyx LES
  • EVOH ethyl vinyl alcohol copolymer
  • Tantalum
  • DMSO dimethyl sulfoxide

5
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)

6
Biocompatibility - hemocompatibility
  • Hemolysis
  • Lee-White clotting time
  • C3a Complement activation

7
DMSO toxicology
  • LD50s 2.5 g-11 g/kg (cats, dogs, monkeys,
    rabbits, and rats)
  • Can cause hemolysis
  • Can be angiotoxic

8
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)

9
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

10
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

11
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

12
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

13
DMSO potential vascular toxicity and concern with
repeat injection
  • Rate
  • Repetition
  • DMSO volumes
  • Number of procedures
  • Indicated as a presurgical tool

14
Additional preclinical testing
  • Effect of radiation on polymer
  • Interaction of DMSO with platinum coils
  • Interaction of DMSO and Cyanoacrylate

15
Conclusions
  • Extensive biocompatibility assessments performed
  • Animal evaluations indicate relative safety
  • DMSO repeat injection concern

16
Clinical review
  • Ann H. Costello, Ph.D., D.M.D.

17
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.
18
Objective Demonstrate that Onyx was no worse
than n-BCA in terms of efficacy within a 20
specified clinical tolerance.
19
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.

20
Patient Accountability
21
Patient Demographics (n102)
22
Medical History (n102)
plt0.05
23
Primary Presenting Symptoms (n102)
24
Pretreament Assessment (n103 AVMs in 102 pts)
25
Pretreament Assessment - cont. (n103 AVMs in
102 pts)
26
Pretreament Assessment - cont. n103 AVMs in
102 pts)
27
Onyx Usage Details
28
n-BCA Usage Details
29
Device Usage
30
Coil Usage
p0.008
31
Endpoints Primary 50 or greater angiographic
reduction in AVM size by core laboratory was
required for success. Secondary Surgical
blood loss Surgical resection time
32
Percentage of Patients with gt 50 Exclusion of AVM
33
Blood Loss Index
p0.55
34
Surgical Resection Time (min)
p0.99
35
Neurological Assessment
36
Neurological Assessment (cont.)
37
Neurological Assessment (cont.)
38
Neurological Assessment (cont.)
39
Physician Ratings of Device Performance
40
Frequency of Complications Cranial

41
Complications Cranial (cont.)
42
Frequency of Complications Cranial
43
Frequency of Complications non-cranial

44
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.

45
Statistical Comments for Onyx Liquid Embolic
System
  • Judy Chen, M. S.
  • OSB/DBS

46
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

47
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.

48
Analyses Populations
  • FDAs ITT (n108) ---All 108 randomized patients
  • Sponsors ITT (n93) ---2 late screen failures,
    6 dural fistulae, 4 films not analyzable and 3
    ongoing were excluded from all randomized
    patients.
  • Sponsors conservative ITT (n96)---Adding 2
    ongoing in the Onyx group (counted as failures)
    and 1 in the control group (counted as success)
    to the above ITT population

49
Sponsors ITT Population (n93)
50
-------continue------ Sponsors ITT Population
(n93)
51
Sponsors ITT Result (n93)
  • Summing total numbers of patients and number of
    successes over 17 centers, and excluding patients
    who were late screen failures (n2), patients
    with dural fistulas (n6) 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).

52
Sponsors conservative ITT Results (n96)
  • 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.

53
Comments for sponsors ITT analyses
  • Original Randomization is not preserved.
  • The center or stratification is ignored.

54
FDAs ITT (All Randomized) (n108)
55
-------continue------ All Randomized (n108)
56
All Randomized (n108) 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 (p0.46).
  • Common Odds Ratio estimate1.55
  • with 1-sided 95 lower limit 0.68.

57
All Randomized (n108) 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.

58
Secondary Endpoints
59
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.

60
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.


61
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.

62
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.

63
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.

64
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 sponsors proposed training
    plan and whether you believe it is adequate to
    help ensure proper device use.

65
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?
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