FDA’s Presentation Barricaid® Anular Closure Device

(M140021/P160050)

Meeting of the Orthopedic and Rehabilitation Devices Panel of the Medical Devices Advisory Committee

Gaithersburg, Maryland December 12, 2017

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Current FDA Review Team • David Hwang, PhD- Lead • John Stinson, MD- Clinical • Pablo Bonangelino, PhD- Statistical • Kimberly Amrami, MD (Special Government Employee)- Musculoskeletal Radiology • Yuzhi (Alex) Hu- Epidemiology • Brent Showalter, PhD- Engineering • Genevieve McRae, PhD- Retrieval Analysis • Sabine Francke, DVM, PhD and Steven Mog, DVM, DACVP- Veterinary Pathology • Katherine Kavlock, PhD- Biocompatibility • Aprajita Garg, PhD- Sterility • Marisa White- Bioresearch Monitoring • Katelyn Bittleman- Manufacturing • Terry Woods, PhD and Maria Iacono- MR Compatibility

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Purpose of Panel Meeting

• Obtain feedback from the Panel regarding aspects of the data provided in support of the Barricaid® Anular Closure Device: – Study population vs. the proposed Indications for Use/Intended

Use – Study endpoints and study duration – Interpretation of study outcomes for P160050 – Significance of endplate lesions in the control and experimental

cohorts – Rate and significance of observed device failures

• Obtain the Panel’s recommendation regarding the Benefit-Risk profile of the Barricaid® Anular Closure Device

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Outline • Device Description • Regulatory History • Clinical Background • Study Overview • Safety Assessments • Endplate Lesions • Effectiveness Assessments • FDA’s Benefit-Risk Assessment

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FDA’s questions to the Panel will be presented in the afternoon. Key points in FDA’s presentation pertaining to the Panel questions will be highlighted in blue boxes at the bottom of the slides.

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DAVID HWANG, PHD LEAD REVIEWER, BIOMEDICAL ENGINEER DIVISION OF ORTHOPEDIC DEVICES OFFICE OF DEVICE EVALUATION

Device Description Regulatory History

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Barricaid® Anular Closure Device • Implant components

– Mesh (PET layers connected with PTFE-coated PET sutures)

– Anchor (Ti alloy) – Marker (PtIr)

• 8mm, 10mm and 12mm width x 15mm length • PMA seeking approval for Generation 3 • Device Specific Instruments:

– Pre-loaded onto a delivery tool – Defect sizing tools – Alignment trials

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Intended Use/Indications for Use

The Barricaid is intended to be implanted following a limited discectomy, to prevent reherniation and the recurrence of pain or dysfunction. The Barricaid is indicated for subjects with radiculopathy (with or without back pain), a posterior or posterolateral herniation, characterized by radiographic confirmation of neural compression using MRI, and a large anular defect (e.g., between 4-6 mm tall and between 6-12 mm wide) determined intraoperatively post discectomy, at one level between L4 and S1.

www.fda.gov The Panel will be asked to make a recommendation on approvability of the PMA based on the proposed

Indications for Use.

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Regulatory History • Intrinsic Therapeutics (sponsor) initially submitted an Investigational

Device Exemption (IDE) to start a clinical trial in the United States – IDE was never approved due to safety concerns – Sponsor performed clinical trials outside of the U.S. (OUS), including a randomized,

clinical trial (RCT), to support initiation of a U.S. clinical study

• FDA and sponsor never reached consensus on OUS study design, associated protocols, or documents (e.g., informed consent) – FDA acknowledges the sponsor incorporated some of the Agency’s feedback from

the IDE into the OUS study protocol

• OUS RCT clinical data and non-clinical studies were submitted in a PMA

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Functional Large Animal Model - Baboon • 9 baboons (3 animals per time point – 3mo,

6mo, 12mo.) – 1 level partial discectomy control – 2 levels Barricaid

• Histopathology, microradiographs, MRI and CT • Progressive inflammation with the highest at 12

months, severity of 4.8/5 • Observed: osteolysis, fibrosis, endplate

disruption, mesh subsidence • Reactive changes in response to the mesh

component: reactive sclerosis on CT and bone marrow edema on MRI

• Endplate lesions at 12 months did not stabilize or diminish when compared to the 3 or 6 month images

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Clinical Background Study Overview Safety Assessments

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JOHN STINSON, MD MEDICAL OFFICER, ORTHOPEDIC SPINE SURGEON DIVISION OF ORTHPEDIC DEVICES OFFICE OF DEVICE EVALUATION

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Pathoanatomy - Lumbar Intervertebral Disc

(Deyo, Mirza 2016) (Fardon et al 2014)

Schmorl Node (Intravertebral Disc Herniation)

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Diagnosis - Lumbar Disc Herniation

Level Sensory Reflex Motor L 3-4 Anterior thigh,

leg Knee Quad

L 4-5 Lateral leg N/A Dorsiflexors L 5-S1 Posterior leg,

sole of foot Achilles Plantar flexors

(Deyo, Mirza 2016)

Herniated L5-S1 Disc

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Treatment Options - Lumbar Disc Herniation

• Favorable natural history in most cases • Non-operative Treatment: Oral meds/supervised exercise/epidural

injections/passage of time • MRI/CT in 4-6 weeks if sciatica persists and invasive treatment is

considered • Early surgery only if severe or progressive neurologic deficit • Elective surgery an option with persistent sciatica • Surgery provides early relief of sciatica • Surgery results at 1 year similar to conservative treatment

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Lumbar Discectomy

• Many techniques are used • Sequestrectomy • Limited Discectomy • Subtotal Discectomy • Others

• Outcomes are all generally favorable, regardless of technique

(Deyo, Mirza 2016)

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Subsequent Surgical Interventions • Spine Outcomes Research Trial (SPORT): reoperation rate 6% at 1 year, 8% at 2

years and 15% by 8 years (Leven 2015)

• 62% of reoperations were for recurrent disc herniation, and most of these occurred within 2 years of index procedure

• Risk of reoperation for recurrent disc herniation: 5% by 2 years, 9% by 8 years • Wide variation in reoperation rates among hospitals and surgeons-unclear and

likely multifactorial (Martin 2012)

• Survey: • First recurrence-revision microdiscectomy • Second recurrence-wide variability (fusion/TLIF/PLIF/revision microdiscectomy) (Mroz 2014)

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Diagnosis: Recurrent Lumbar Disc Herniation

• Variable Definitions for Reherniaton: – New herniation @ same level – Same side as index surgery vs. contralateral – Pain free interval >3 weeks to 6 months – Return of symptoms consistent with previous

presentation in the same patient – Radiographic vs. Symptomatic

• Imaging is used to confirm, usually MRI

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Sponsor Proposed “At-Risk Population”

Small annular defect-low risk (<6mm) Large annular defect-high risk (≥6mm)

(From Barricaid PMA) www.fda.gov

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Carragee Classification (2003) (N=180) Herniation Type Anular

Competence Surgical Treatment Incidence

(n) Reherniation Rate (n)

I: Fragment-Fissure Slit-like/small (Yes)

Removal of fragments through slit-like anular defect

49% (89) 1% (1)

II: Fragment-Defect Large/massive (Yes)

Removal of fragments through massive anular defect

18% (33) 27.3% (9)

III: Fragment-Contained

No defect (Yes)

Oblique incision in anulus performed to remove subanular fragments

23% (42) 9.5% (4)

IV: No Fragment-Contained

No defect (No)

Extensive anulotomy/ removal of protruding disc

9% (16) 12.5% (2)

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Study

Symptomatic Reherniation

Symptomatic Reherniations with Large Anular Defects

Definition of Large

Anular Defect

Study

Duration Carragee, 2003 8.9% 22% ˃ 6 mm (2 planes) 2 Years Carragee, 2006 14% 18% ˃ 6 mm 2 Years Zhou, 2016 8% 15% ˃ 6 mm 2 Years Kim, 2013 8% 18% ˃ 6 mm 6 years Boyaci ,2016 4% 6.5% ≥ 5 mm 2 years McGirt, 2009 10.2% 18% ˃ 54 mm sq.

(top quartile) 2 years

Wera, 2008

4.5% 2.3% Fragment-Defect/ No Fragment-Contained

15 years

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Literature on Large Anular Defects

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Barricaid Clinical Study

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Barricaid Study Design

• OUS multi-center, prospective, randomized (1:1), largely unmasked, concurrently controlled superiority clinical trial

• Objective: To evaluate the safety and effectiveness of the Barricaid following a limited discectomy in preventing reherniation and SSI, compared to a limited discectomy alone in lumbar disc surgery patients with large annular defects

• 554 randomized subjects at 21 OUS clinical sites • 42 Generation 2 and 225 Generation 3 devices implanted

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Key Inclusion Criteria • Subjects with posterior or posterolateral disc herniations at

one level between L1 and S1 with radiographic confirmation of neural compression using MRI, no response to 6 weeks non-operative care

• Radiculopathy (with or without back pain) with a positive Straight Leg Raise (0 – 60 degrees) (L4-5, L5-S1) or Femoral Stretch Test (L1-2, L2-3, L3-4)

• Patients with an anular defect (post discectomy) between 4mm - 6mm tall and 6mm - 10mm wide

• ODI, VAS Leg pain (one or both legs) ≥ 40 at baseline

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Key Exclusion Criteria • Prior surgery at the index lumbar vertebral level • DEXA T-score ˂ -2.0 at index level; metabolic bone disease; pathologic

vertebral fractures • Scoliosis ˃ 10˚ • Spondylolisthesis ≥ 25% • Cauda equina syndrome • Diabetes (insulin-dependent); RA; peripheral vascular disease;

peripheral neuropathy; received steroids >1 month over the past year • Morbid obesity

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Screening, Enrollment and Randomization

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Patients who “presented to the clinic with complaints concordant with a herniated lumbar disc”

Met pre-operative inclusion/exclusion criteria

Implantation of Barricaid Device Barricaid Group

Control Group

Proceeded to surgery: Limited Discectomy

Did not meet pre-operative inclusion/exclusion criteria

Screened Enrolled

Met intra-op inclusion criteria (e.g. size, approach)

Did not meet intra-op criteria

Randomized

Measure Defect Size

No additional action

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Study Treatments Control: Limited Discectomy as described by Spengler et al.

“After adequate lateral wall exposure was obtained, the dural sac and the nerve root were retracted medially, and the pathologic changes in the disc were identified. If the disc was sequestered, the free fragment was removed but the annulus was not entered. In cases of extruded disc herniations, the extruded fragment was excised, and loose fragments near the annular defect were removed with a small pituitary rongeur. When a protruded disc was identified, the annulus was incised, and removal of all loose disc tissue was performed. After disc removal, the neural foramen was assessed.”

Barricaid Group: Spengler Limited Discectomy and implantation of Barricaid

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Evaluation Schedule/Key Assessments Assessment Prior to

Surgery Day of Surgery 12

Months 24, 36, 48 & 60

Months Pre-operative

screening X

Intra-operative screening

X

Case Report Forms X X X X

VAS, ODI, SF-36 X X X X

Neurologic status X X X X

Adverse Events (if applicable)

X X X

MRI X X X

CT X X X

X-rays X X X www.fda.gov

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Clinical Protocol Definition Endpoints (Pre-specified)

1st Co-Primary Endpoint - Reherniation at 24 Months: “Reherniation: To be considered a success, a patient will have no

evidence of recurrent herniation at the index level at any time up to and including the 24-month follow-up. Recurrent herniation may be confirmed surgically, or radiographically as determined by an independent review (unless surgically confirmed that the suspected herniation is not a herniation, e.g. scar tissue or residual nucleus material).”

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Clinical Protocol Definition Endpoints (pre-specified) 2nd Co- Primary Endpoint:

Composite Clinical Success – Clinical Protocol Definition (CCS-CPD) Composite Endpoint Component (CCS-CPD)

Success Criteria

Reherniation Success No reherniation at the index level (Includes all reherniations, regardless of symptoms)

Safety Success No secondary surgical interventions (SSIs) at the index level

Radiographic Success: Disc Height Spontaneous fusion Device integrity

Maintenance of ≥ 75% pre-op No spontaneous fusion No disassembly or migration

Neurologic Success No deterioration at the index level Functional Success ODI VAS-Leg

↓≥ 15 point (out of 100) ↑≥ 20 point (100 point scale)

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post hoc Composite Clinical Success Modified Clinical Protocol Definition (CCS-mCPD)

Composite Endpoint Components (CCS-mCPD)

Success Criteria

Symptomatic Reherniations No symptomatic reherniation at the index level

ODI ↓≥ 15 points (out of 100) Neurologic No deterioration at the index level SSIs at index level No SSIs at the index level Device or procedure-related SAEs No device or procedure related SAEs

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Symptomatic Herniation Definition

Points of Uncertainty:

• Any unscheduled visits • Any lumbar-related pain • Non-specific symptoms • No physical exam

required

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Differences Between Protocol and Modified Study Endpoints

Protocol Definition Modified Definition No Reherniation (all) No Reherniation (only symptomatic) ODI ↓ ≥ 15 points ODI ↓ ≥15 points No ↓ neurologic function No ↓ neurologic function No SSI No SSI VAS-Leg ↓ ≥ 20 mm No Device or Procedure-related SAEs Disc height ≥ 75% No Spontaneous fusion Device Integrity

There will be a Panel question regarding appropriate endpoints to be used to evaluate the safety and efficacy of an anular closure device.

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Radiographic Assessments

• Disc Height • Spontaneous Fusion • Device Integrity (Condition/Migration) • Sagittal Disc Angle • Spondylolisthesis • Modic Changes • Annular Tears/Fissures

• Disc Degeneration (Pfirrmann Grade) • Ossification (Anterior and Posterior) • Endplate Lesions – Area (sagittal, axial and coronal) – Septation – Mineralization – Reactive Perilesional Changes

(edema or sclerosis)

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Enrolled Patient Population and Demographics

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Enrollment & Randomization – Study Population

Screened: 3,332

Enrolled : 647

Enrolled but not randomized: 93 Defect too large-49 Defect too small-26 Other-18 (e.g. two-level, no herniation)

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Month 12 Month 24 Month 36 Month 48 Month 60

I C I C I C I C I C

(1) Theoretical 272 278 272 278 253 258 181 184 108 109

(2) Not Yet Overdue 0 0 0 0 4 9 6 9 12 9

(3) Deaths and SSI Failures 23 35 29 45 32 49 33 33 20 17

(4) Expected Due = (1) – (2) –(3) 249 243 243 233 217 200 142 142 76 83

(5) Expected Due + SSI Fail 271 278 271 278 248 249 174 175 96 100

(6) Any data in interval 240 230 228 211 163 134 99 95 48 54

(7) Any data within window 229 216 203 188 139 109 82 75 36 42

(8) CCS-CPD --- --- 245 259 202 216 144 155 80 89

(9) Actual % FU for CCS-CPD --- --- 90% 93% 81% 87% 83% 89% 83% 89%

Patient Accounting

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Demographic Profile

• No statistical differences between treatment groups in baseline functional outcome scores, comorbidities or demographics

• Similar baseline data for work status, medication usage and symptom duration

• Overall 98.7% Caucasian • Overall 44% current smokers, 63% current or former smokers

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Intraoperative Data - Anular Defect

Anular Defect Type Barricaid Study (N=550)

Carragee Study (2003)

n % % I: Fragment-Fissure 0 0% 49%

II: Fragment-Defect 345 63% 18%

III: Fragment-Contained 204 37% 23%

IV: No Fragment-Contained 1 0.2% 9%

Enrolled but not randomized: 93 • Defect too large-49 • Defect too small-26 • Other-18 (e.g. two-

level, no herniation)

The Panel will be asked a question that includes discussion regarding whether the studied patient population is representative of the US population.

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Intraoperative Data: Anular Defect Assessment

Overall Barricaid Control

Anulotomy Geometry

Box 341 (62%) 182 (67%) 159 (57%)

Cruciate 29 (5.3%) 11 (4%) 18 (7%)

Puncture/Slit 155 (28%) 65 (24%) 90 (32%)

None 25 (4%) 14 (5%) 11 (4%)

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Intraoperative Data: Anular Defect Assessment

Overall Barricaid Control Defect Width

6mm 93 (17%) 49 (18%) 44 (16%) 7mm 120 (22%) 65 (24%) 55 (20%) 8mm 173 (32%) 88 (32%) 85 (31%) 9mm 82 (15%) 37 (14%) 45 (16%)

10mm 82 (15%) 33 (12%) 49 (18%) Defect Height

4mm 169 (31%) 83 (31%) 86 (31%) 5mm 271 (49%) 136 (50%) 135 (49%) 6mm 110 (20%) 53 (20%) 57 (21%)

There will be a Panel question regarding the procedures conducted on the study

population and whether this was representative of the intended

population, particularly the study control group.

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Safety Results

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Safety Evaluation

• Adverse Events (AEs) –Serious AEs (SAEs) –Device or Procedure-Related AEs

• Subsequent Surgical Interventions (SSIs) • Device Integrity • Endplate Lesions

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Adverse Events (AEs)

Barricaid Control Events Subjects % Events Subjects %

Any AE 626 222 83 564 221 78

Any Device-Related AE 345 178 67 9 6 2

Any Procedure-Related AE 377 185 69 337 179 63

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Notable Adverse Events

AE Barricaid Control ∆

Events n % Events n %

Device Deficiency 35 34 13.1 1 1 0.4 12.8%

Disc Herniation 66 52 24.7 109 88 38.5 -13.8%

Wound Issue: SSI at index level 26 22 9.7 22 19 7.8 2.0%

Bone Necrosis/Resorption 52 49 19.5 4 4 1.4 18.1%

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Serious Adverse Events (SAEs)

SAE Barricaid (N=267) Control (N=283)

Events n % Events n %

All SAE 187 100 38% 190 116 41%

Device or Procedure-related SAE 78 47 18% 108 71 25%

Device-related SAE 72 45 17% 3 2

Procedure-related SAE 77 47 18% 108 71 25%

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Secondary Surgical Interventions (SSIs)

Months

Barricaid (event) Control (event) ∆ N n % N n %

12 243 17 6.5 232 35 13% -6.4%

24 216 23 8.8 202 44 16.4 -7.5%

36 153 27 11 143 51 20 -9.2%

48 94 34 15.6 91 55 23 -7.3%

60 30 38 19 32 57 25.5 -6.5

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SSI Survival Estimates

Year

Barricaid (N=267) Control (N=278)

% Lower Bound

Upper Bound

% Lower Bound

Upper Bound

1 94 90 96 87 83 91

2 91 87 94 84 79 88

3 89 85 93 80 75 85

4 84 79 89 77 71 82

5 81 74 86 75 67 80

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2°, 3° and 4° Surgical Interventions Procedure Initial

SSI 2° SSI 3° SSI 4° SSI

Barricaid Group All SSI 38 9 2 0 Discectomy +/- removal 23 0 0 0 Supplemental fixation +/- discectomy +/- removal

12 8 1 0

Other* 3 1 1 0 Control Group

All SSI 57 16 4 2 Discectomy 38 5 1 0 Discectomy + Barricaid 5 0 0 0 Supp. Fixation +/- discectomy 6 8 1 1 Other* 8 3 2 1 *Other - other decompression,

wound, hematoma

There will be a Panel question regarding interpretation of

endpoints, which includes SSI which have traditionally all been

considered failures. Please consider additional discussion regarding

whether SSIs should all be considered equal weight when

evaluating Benefit-Risk.

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Safety Evaluation - Endplate Lesions • EPLs identified as a safety concern. • Safety concern since baboon and previous OUS feasibility studies. • Total of 673 EPLs identified by the sponsor’s core lab as existing at one or

more time points (Both AT Barricaid and Control groups). • 483 EPLs observed in 235 (88%) Barricaid AT patients and 190 EPLs observed in 113 (39%) control subjects. • Lesion characteristics

– Barricaid group: larger on average, faster growth that appears to stabilize around year 4-5

– Control group: smaller on average, does not grow much after initial identification, shows a greater sign of shrinking at later time points

• The sponsor has done exhaustive analyses and has found no clinical implications from the presence, location or size of EPLs.

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KIMBERLY AMRAMI, MD MUSCULOSKELETAL RADIOLOGIST SPECIAL GOVERNMENT EMPLOYEE (SGE)

Qualitative Analysis of Endplate Lesions

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Qualitative Radiographic Assessment • Member of FDA review team as a special government employee

– Involved with previous IDE and pre-submissions for Barricaid • Tasked to independently review the images for qualitative

features – Review of image set for individual subjects in following groups:

• Barricaid subjects with endplate lesions opposed to the mesh (40) • Barricaid subjects without endplate lesions (12) • Control subjects with and without endplate lesions (11)

• Emphasis on CT across all available time points – X-ray and MRI used as secondary sources

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Categorization of Radiographic Findings • All findings were presented by sponsor as “endplate changes” • Opinion of sponsor’s radiographic protocol

– Measurements such as sclerotic margin, Modic changes, and septations did not clearly outline the visually distinct groups

– Conflation of endplate lesions associated with the mesh with Schmorl’s nodes (separation is possible) and endplate changes

• Three distinct groups were revealed during qualitative assessment – Endplate Changes – Endplate Lesions (Schmorl’s Nodes) – Lytic Lesions

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Observed Radiographic Categories Endplate Changes Lytic Lesion Mesh Opposing

Vertebral Body Endplate Lesion/Schmorl’s Node

• Low density on CT • Well-formed sclerotic margin • Not present at baseline • Often progressive in size

• Alternative term for Schmorl’s nodes* • Typically well defined sclerotic margin • More discrete than endplate changes • Correlation on MRI, confirming

presence of disc material • Stable over time

• Generally related to disc degeneration and disc space narrowing

• More diffuse than typical lytic lesions or Schmorl’s nodes

• May improve over time

(Newell et al. 2015) www.fda.gov

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Endplate Changes

• Present in both Barricaid and control groups – Present at baseline – Present at multiple levels – Present on both sides of the index level

• Most common in control patients

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Control Subjects with Endplate Changes

CT at Baseline CT at 12 months CT at 36 months CT at 48 months

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Endplate Lesions

• Accepted term for Schmorl’s Nodes* • Present in both Barricaid and control groups

– Present at baseline – Present at multiple levels – Present on both sides of the index level

(Newell N et al. 2015) www.fda.gov

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MRI at 12 months CT at 12 months

Barricaid Subject with Endplate Lesion (Schmorl’s Node)

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Lytic Lesions

• All cases were found in Barricaid subjects • Associated with the vertebral body opposite

of the mesh – Rare instances associated with anchor

• Subcategory: subsidence of the mesh beyond the cortex of the vertebral endplate – Degree of subsidence limited by the length of the

mesh

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Barricaid Subject with Lytic Lesion and Subsidence

CT at Baseline CT at 12 months CT at 24 months CT at 60 months

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Barricaid Subject with Lytic Lesion

Subsidence at year 5

CT Baseline CT 12 months CT 48 months CT 60 months

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Conclusions on Qualitative Radiographic Assessment

• Lytic lesions are radiographically distinct from Schmorl’s nodes and endplate changes – Seen only in Barricaid subjects

• Lytic lesions are progressive in size • Lytic lesions are commonly associated with subsidence of the

mesh beyond the vertebral cortex • Not all lytic lesions stabilize in size by year 5

– Subsidence may occur as late as year 5

The Panel will be asked to comment on safety concerns regarding endplate lesions. www.fda.gov

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Quantitative Analysis of Endplate Lesions

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Quantitative Analysis of EPLs

• Methods for measuring the size of EPLs – Slice with the largest EPL in each plane – Area estimated as an ellipse (major and minor axis)

• Analysis done on per subject and per lesion • Growth rates examined • Correlation with clinical outcomes were investigated including

many sub-categories (e.g. mesh proximate, mesh subsided)

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Endplate Lesion Size Median Endplate Lesion Size (mm2) – 3 plane average

Barricaid Barricaid – Mesh Proximate

Control

N Med Max N Med Max N Med Max

Baseline 63 33 255 --- --- --- 55 34 324

Month 12 265 44 328 94 82 328 110 35 468

Month 24 333 46 325 109 93 325 107 33 398

Month 36 193 53 308 67 98 308 75 48 336

Month 48 102 67 302 28 118 302 49 27 263

Month 60 29 67 283 8 135 283 16 35 155 www.fda.gov

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Endplate Lesion Growth Rates Median Endplate Lesion Growth Rates Per Subject (mm2/year) – 3 plane average

Barricaid Barricaid mesh proximate Barricaid mesh prox. w subsidence

Control

N Med Q3 Max N Med Q3 Max N Med Q3 Max N Med Q3 Max

Months 0 - 12 177 67 99 366 112 82 115 366 79 87 124 366 71 19 51 266

Months 12 - 24 204 30 62 207 125 37 72 207 83 41 72 192 87 4 24 311

Months 24 - 36 145 16 42 265 88 19 51 265 64 27.2 54 265 55 10 29 204

Months 36-48 74 9 27 180 45 12 32 125 37 6 35 125 37 7 17 143

Months 48 - 60 34 4 14 74 19 4 27 74 16 1.8 11 62 21 -7.5 4 74

There will be a Panel question regarding appropriate study length to evaluate the device.

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Correlation Analysis of Endplate Lesions • The sponsor explored Composite Clinical Success and its components for the following subgroup

comparisons:

– “Barricaid with EPL” to “Control with EPL”; – “Barricaid with EPL” to “Control without EPL”; – “Barricaid with EPL” to “Barricaid without EPL”; – “Control with EPL” to “Control without EPL”; – “Barricaid Mesh-Opposed EPL” to “Barricaid Non-Mesh Opposed EPL” – “Control Mesh-Opposed EPL” to “Control Non-Mesh Opposed EPL”; and, – “Barricaid Mesh-Opposed EPL” to “Control Mesh-Opposed EPL”

There were two notable findings: • Mesh-proximate Barricaid lesions associated with lower rates of maintenance of average disc height • Lesions in the Control group associated with higher rates of symptomatic vs. asymptomatic reherniation • However, these may be due to chance. The reherniation finding was not replicated in the Barricaid data. www.fda.gov

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Correlation Analysis- Endplate Lesion Types Endplate Lesion Subgroup Outcomes Analyzed

All lesions Primary Month 24 CCS

Mesh-proximate Modified Month 24 CCS

Mesh-proximate with subsidence No SSI / Time to SSI

Large (> 100mm2) No Reherniation / Time to Reherniation

Large mesh-proximate No Symptomatic Reherniation

Large mesh-proximate with subsidence No Asymptomatic Reherniation

Time to Device Integrity Failure

There were no notable findings and specifically no correlations between EPL’s and clinical outcomes, except for a correlation between EPL’s and symptomatic reherniation in the Control group, as described in the previous slide.

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JOHN STINSON, MD MEDICAL OFFICER DIVISION OF ORTHOPEDIC DEVICES OFFICE OF DEVICE EVALUATION

Effectiveness Results

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Clinical Protocol Definition Endpoints (prespecified)

Co-Primary Endpoint: No Reherniation at 24 Months : Reherniation Success (asymptomatic or symptomatic)

Barricaid 50.8% Control 30.1%

There will be a Panel question regarding utility of this endpoint, and whether it should be considered in the evaluation of the device.

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Composite Clinical Success CCS-CPD @24 months

Measure Barricaid (%) Control (%) ∆ p-value

No reherniation (all) 50.8 30.1 20.7 ˂0.001 ODI decrease ≥ 15 points 93.4 94.8 -1.4 0.545 VAS-Leg decrease ≥20 mm 94.7 96.2 -1.5 0.454 No SSI 91.4 83.8 7.6 0.007 Neuro ≥ baseline 98.0 95.2 2.8 0.083 Disc height ≥ 75% baseline 65.4 67.3 -1.9 0.354 No fusion 100 99.6 3.4 - Device integrity 86.8 N/A N/A N/A

Overall Success 27.8 18.1 9.7 0.010 www.fda.gov

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post hoc Modified Clinical Composite Success CCS-mCPD @24 months

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Measurement Barricaid (%) Control (%) ∆ Nominal p-value

No symptomatic reherniation 88.8 74.6 14.2 ˂0.001

No SSI 91.4 83.8 7.6 0.007 No device or procedure-related SAE

87.1 79.5 7.6 0.016

Neuro ≥ baseline 98.0 95.2 2.8 0.083

ODI decrease ≥ 15 points 93.4 94.8 -1.4 0.545

Overall Success 75.9 63.9 12 0.003

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Longer-Term Success - Device Related Endpoints and CCS-CPD

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Endpoint Barricaid Control

12 M 24 M 36 M 48 M 60 M 12 M 24 M 36 M 48 M 60 M

No Reherniation

66% (163/247)

50.8% (122/240)

35% (68/195)

27.7% (38/137)

14.7% (11/75)

39% (99/254)

30.1% (122/240)

18.4% (40/217)

10.4% (16/154)

8.4% (8/95)

No SSI 93.5% (250/267)

91.4% (244/267)

89.5% (222/248)

84.7% (149/176)

83.8% (88/105)

87.2 (243/278)

91.4% (233/278)

81.0% (209/258)

82.1% (151/184)

84.4% (92/109)

Device Integrity 95.2% (238/252)

87% (210/242)

79.7% (137/172)

73.0% (84/115)

58.3% (35/60)

N/A

Overall Success 48% (122/254)

27.8% (68/245)

7.4% (15/204)

6.8% (10/146)

4.8% (4/84)

27.4% (71/259)

18.1% (47/259)

6.3% (14/222)

1.9% (3/160)

1.0% (1/96)

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Longer-Term Success - Device Related Endpoints and

post hoc CCS-mCPD

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Endpoint Barricaid Control

12 M 24 M 36 M 48 M 60 M 12 M 24 M 36 M 48 M 60 M

No Symptomatic Reherniation

91.9% (227/247)

88.7% (213/240)

82.6% (161/195)

78.8% (108/137)

74.7% (56/75)

78.7% (200/254)

74.6% (213/240)

67.7% (147/217)

70.1% (108/154)

70.5% (67/95)

No SSI 93.5% (250/267)

91.2% (244/267)

89.5% (222/248)

84.7% (149/176)

83.8% (88/105)

87.2 (243/278)

91.4% (233/278)

81.0% (209/258)

82.1% (151/184)

84.4% (92/109)

Overall Success 78.8% (204/259)

75.9% (192/253)

66.8% (127/190)

62.0% (80/129)

50.0% (35/70)

68.1% (177/260)

63.9% (163/255)

51.3% (98/191)

52.2% (70/134)

49.3% (37/75)

There will be Panel questions regarding appropriate endpoints and appropriate study length to evaluate the device.

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Individual Endpoint – All Reherniations

Year

Barricaid (N=267) Control (N=278)

% Lower Bound

Upper Bound

% Lower Bound

Upper Bound

1 66 60 71 39 33 45

2 45 45 57 31 25 37

3 42 36 49 23 17 28

4 36 29 43 16 11 22

5 26 17 36 14 9 20

Year

Barricaid Control

N n % N n %

1 247 84 34 254 155 61

2 240 118 49 256 179 70

3 195 127 65 217 177 82

4 137 99 72 154 138 90

5 75 64 85 95 87 92

All Reherniations All Reherniations – Survival Estimate

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74

Individual Endpoint – Symptomatic Reherniations

Year

Barricaid (N=267) Control (N=278)

% Lower Bound

Upper Bound

% Lower Bound

Upper Bound

1 92 89 95 79 74 84

2 89 85 93 75 69 80

3 83 78 88 70 64 76

4 81 75 86 67 61 74

5 73 65 63 64 56 72

Year

Barricaid Control

N n % N n %

1 247 20 8 254 54 21

2 240 27 11 256 65 25

3 195 34 17 217 70 32

4 137 29 21 154 46 30

5 75 19 25 95 28 30

Symptomatic Reherniations Symptomatic Reherniations – Survival Estimate

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Individual Endpoints – Device Integrity

By 24 Months After 24 Months N n % SSIs N n % SSI

Device Integrity Failure 242

32

13.2%

13

164

16

10

4

Condition Failure (Fracture or disassembly)

238

11

4.6%

162

3

1.9%

Migration Failure (anchor, mesh, both)

243

29

11.9%

162

14

8.6%

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76

Example of Migration

Post Op 6 Months 12 Months www.fda.gov

77

Device Integrity

• By 24 months successful clinical outcomes seen in 20/32 (64%) of device failure patients

• 5/20 initially successful subjects with device integrity failure went on to have SSI after 24 months

• Success of initial procedure is due to the discectomy & root decompression

Utility of Device integrity as an endpoint should be considered during Panel questions discussing appropriate endpoints.

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78

Device Failures: Retrieval Analysis • Collected 63 implant and instrument retrievals during the OUS

study and commercial use, 21 reports provided

• Average retrieval was 2.4±1.8 years (Range = 0.1-5.8 years) after implantation

• Implant removed primarily due to mesh detachment, migration, new or worsening pain and/or instability

• Similar failures between Gen 2 and Gen 3 devices, despite strengthened attachment

• Mesh fraying in 19/21 analyzed implants

• Seven of the retrieved implants were due to the mesh migrating into neural structures

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Device Failures: Peri-Prosthetic Tissue • 11/21 included peri-prosthetic tissue which was analyzed

with histopathology • Agency found 9/11 included tissue from around the mesh

that showed signs of inflammation • 7/9 with inflammation had evidence of mesh particles

within multinucleated giant cells and macrophages • Limitations include relative few samples, poor description of

where tissue samples were taken, etc. • Supported by similarities seen in the baboon study

There will be a Panel question regarding safety concerns of the endplate lesions.

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80

JOHN STINSON, MD MEDICAL OFFICER DIVISION OF ORTHOPEDIC DEVICES OFFICE OF DEVICE EVALUATION

Benefit-Risk Assessment

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Barricaid Benefit-Risk Assessment

Benefits (24 Months) • ↓ All Reherniations by 20.7% • ↓ Symptomatic reherniations by

14.2% • ↓ SSIs by 7.6% • ↓ SSIs for reherniation by 7.9% • ↓ Device or procedure-related SAEs

Risks • >Supplemental Fixation SSI • Device integrity failures • Endplate Lesions • Bone necrosis/resorption

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Other Considerations • Uncertainty with many aspects of the clinical data:

– Definition of the “at-risk” patient population – Whether the study population adequately evaluated the target condition – Whether the study population is representative of US target population – Whether the surgical technique for discectomy was consistent and

representative of US practice – Whether appropriate study endpoints were evaluated – Whether discectomy, fusion, and removals should be given equal weight in

the assessment of subsequent surgical interventions – Adequacy of study duration, especially in view of the presence of EPLs – Incomplete blinding of subjects and investigators

• Relatively young intended target population for Barricaid www.fda.gov

83

DAVID HWANG, PHD LEAD REVIEWER DIVISION OF ORTHOPEDIC DEVICES OFFICE OF DEVICE EVALUATION

Post Approval Study

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84

Reminder

• The discussion of a PAS prior to FDA determination of device approvability should not be interpreted to mean FDA is suggesting that the device is safe and effective.

• The plan to conduct a PAS does not decrease the threshold of evidence required by FDA for device approval.

• The premarket data submitted to the Agency and discussed today must stand on their own in demonstrating a reasonable assurance of safety and effectiveness and an appropriate benefit/risk balance.

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Proposed Post-Approval Studies

• Long-Term Follow-Up: OUS RCT study subjects followed to 5 years to demonstrate safety and effectiveness is maintained through 5 years when compared to control

• New Enrollment: Confirm Barricaid performance in PAS is not inferior to OUS study – Proposed objective should be addressed prior to approval and not part of PAS – Differences between the study population and the intended US patient

population, difficulties in extrapolating from different endpoints used to support OUS review standards, and differences in disease characteristics and treatment standards should be resolved when leveraging OUS data for pre-market approval.

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DAVID HWANG, PHD LEAD REVIEWER DIVISION OF ORTHOPEDIC DEVICES OFFICE OF DEVICE EVALUATION

Concluding Remarks

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87

Study Population Please consider: • Whether the screening processes and discectomy procedures

conducted led to subjects that are representative of the US population

• Whether the discectomies performed are consistent with the described procedure

• Whether the reherniation rate in the control population was influenced by extent of anular resection

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88

Endplate Lesions Please consider: • Whether data are adequate to determine that specific radiographic

findings (i.e. lytic lesions) are associated with the presence of the Barricaid device and absent from the control group – Whether there are the safety concerns associated with these device specific

lesions – Whether the appropriate data was measured to evaluate the safety concerns – Whether the data presented regarding endplate lesions provide reasonable

assurance that the Barricaid device is safe – Whether there are unresolved or long-term safety concerns, and if so, what

additional information is needed www.fda.gov

89

Study Endpoints Please consider: • The appropriate measures to evaluate this device

– Significance of device integrity failures – Ability to interpret positive clinical outcomes regardless of device integrity – Inclusion of clinical outcomes are attributable to discectomy alone – Utility of measuring all reherniations vs. only symptomatic herniations vs. both – The most appropriate definition of symptomatic reherniation, and whether it can be

retroactively applied to the dataset • Adequacy of study duration

– Influence of Endplate Lesions (number, size, progression, chronic inflammation) • Whether discectomy, fusion, and removals should be given equal weight in

the assessment of subsequent surgical interventions www.fda.gov

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References • Deyo, R, Mirza S. Herniated Lumbar Intervertebral Disk. N Engl J Med 2016; 374: 1763-72. • Fardon D et al. Lumbar disc nomenclature: version 2.0 Recommendations of the combined task forces of the North

American Spine Society, the American Society of Spine Radiology and the American Society of Neuroradiology. Spine 14 2014: 2525-45

• Leven, D., et al., Risk Factors for Reoperation in Patients Treated Surgically for Intervertebral Disc Herniation: A Sub analysis of Eight-Year SPORT Data. J Bone Joint Surg Am, 2015. 97 (16): p. 1316-25.

• Martin B et al. Repeat surgery after lumbar decompression for herniated disc: the quality implications of hospital and surgeon variation. Spine J 2012; 12:89–97.

• Mroz, T.E., et al., Differences in the surgical treatment of recurrent lumbar disc herniation among spine surgeons in the United States. Spine J, 2014. 14(10): p. 2334-43.

• Newell, N, et al., A semiautomatic method to identify vertebral end plate lesions (Schorl’s nodes). Spine J, 2015. 15:1665-1673.

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FDA’s Panel Questions

David Hwang, PhD Lead Reviewer

Division of Orthopedic Devices Office of Device Evaluation

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93

Non-Voting Question 1 1. The sponsor planned to enroll a study population that includes subjects with an increased risk of disc reherniation (i.e. large annular defects defined as between 4-6 mm tall and 6-12 mm wide post-discectomy) that would potentially benefit from a permanent implant to prevent reherniation compared to discectomy alone. After review of the data summarized in Section of FDA’s Executive Summary, it appears that patients were enrolled consecutively across multiple sites, and the enrolled study population differed from prior literature reports regarding the incidence of “at risk” disc herniations types as identified by Caragee (2003). For example, the Barricaid study had a much lower number of “fragment-fissure” type anular defects which are associated with a low rate of recurrent lumbar disc herniation in the enrollment population.. Additionally, the majority of study subjects appeared to receive anulotomies (box and cruciate shape) during the discectomy procedure, prior to randomization, which suggests surgical resection of disc annulus beyond the extent required for performing a limited discectomy as defined by the sponsor. Based on the observations regarding the study population described above and in Section 3.1 of FDA’s Executive Summary, please comment on the following:

a. Please discuss the patient characteristics, herniation types, and size and types of anular defects that would

likely benefit from an annular closure device and if that population was adequately investigated in this study.

b. Please comment on the differences noted between the limited discectomy procedures reported in the literature compared to the treatment received by those enrolled in the Barricaid study. Then, please discuss whether the differences had an effect on the clinical outcomes, especially with respect to reherniation rates and subsequent surgical interventions in the control group.

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Non-Voting Question 2 2. The sponsor reported 40% of control patients with an end-plate lesion (EPL), compared to 88% of Barricaid patients. Furthermore, the control patients with EPLs have lesions that are smaller, eventually show signs of reduction in size, and present features more in line with Schmorl’s nodes. In contrast, the EPLs of the Barricaid patients are larger than those of the control, progress in size faster, have radiographically distinct features (e.g., lytic features and a location in proximity to the mesh), and show signs of mesh subsidence into the lesion. However, based on the secondary analyses performed by the sponsor, there does not appear to be a correlation between the presence of EPLs and measured clinical study outcomes. Based on the observations regarding EPLs highlighted in Section 3.2 of FDA’s Executive Summary, please address the following:

a. Please comment on any present and future clinical impact or relevance of the EPLs.

b. Please comment on any additional analyses (e.g., which assessments at what time points),

that should be conducted to evaluate the clinical significance of the EPLs.

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Non-Voting Question 3 3. As summarized in Section 3.3 of FDA’s Executive Summary, the co-primary endpoints developed a priori included a measure of radiographic reherniation rate designed to capture all disc reherniations (symptomatic and asymptomatic) in order to measure device effectiveness at 24 months. Radiographic endpoints to evaluate device integrity (i.e. migration, dissociation) were also included to evaluate the device function, though positive clinical outcomes occurred regardless of device integrity. In addition, the sponsor reported results from an alternative primary endpoint developed post-hoc that focused on symptomatic reherniations at 24 months. Please discuss the following:

a. Please discuss all appropriate endpoint(s) (both safety and effectiveness) for an anular closure

device, and the control population, the time point(s) at which the endpoint(s) should be evaluated and whether these should be the same.

b. Please provide the specific criteria that should be included in a definition of symptomatic recurrent lumbar disc herniation for the anular closure device and the control.

c. While both a secondary discectomy and a secondary procedure that results in a supplemental fixation/fusion are typically counted as failures, should they be given equal weight in discussing risks accrued from implanting a device?

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Voting Questions

The Barricaid is intended to be implanted following a limited discectomy, to prevent reherniation and the recurrence of pain or dysfunction. The Barricaid is indicated for patients with radiculopathy (with or without back pain), a posterior or posterolateral herniation, characterized by radiographic confirmation of neural compression using MRI, and a large anular defect (e.g., between 4-6 mm tall and between 6-12 mm wide) post discectomy, at one level between L4 and S1. Please vote on the following:

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Voting Question 1

a. Is there a reasonable assurance that the Barricaid is safe for the indication for use in patients who meet the criteria specified in the proposed indications?

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Voting Question 2

b. Is there a reasonable assurance that the Barricaid is effective for use in patients who meet the criteria specified in the proposed indications?

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Voting Question 3

c. Do the benefits of the Barricaid outweigh the risks for use in patients who meet the criteria specified in the proposed indications?

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