Clinical Review Barbara Buch, M.D. Orthopaedic Surgeon FDA Orthopaedic Devices Branch

Clinical ReviewClinical Review

Barbara Buch, M.D.

Orthopaedic Surgeon

FDA Orthopaedic Devices Branch


• Clinical Summary• Highlights of Effectiveness and Safety

• Radiographic Interpretation: Summary of Additional information

• Radiographic Interpretation: Considerations for Panel Discussion

Clinical SummaryClinical Summary

• prospective• randomized• multi-center• concurrently controlled• independent radiologists• Bayesian statistical analysis• high patient & data accountability• meticulous adverse event reporting


Open Surgical ApproachInvestigational Control

LaparoscopicInvestigational

n 143 136 134

devicecage +

BMP/ACScage +

autograftcage +

BMP/ACS

follow-up 91% 87% 76%*

* Not all patients were due for 24-month evaluation

Clinical EndpointsClinical Endpoints

primary• fusion• Oswestry pain &

disability• neurologic status• adverse events• 2nd surgeries

secondary• disc height• General Health

Status• back & leg pain• patient satisfaction• patient global

perceived effect• antibody testing• donor site pain

Accountability at 24 monthsAccountability at 24 monthsRandomized PatientsRandomized Patients

• patient 87 - 91%

• data– primary endpoints 90-95%– secondary endpoints > 89%

• antibody testing > 91% all groups

ResultsResultsEquivalent FindingsEquivalent Findings

• demographics

• co-morbidity

• pre-op medical conditions

• diagnostic factors

• levels treated

• use of post-op bracing

• pre-op evaluations

ResultsResultsIntraoperativeIntraoperative

Investigational group• less EBL• less overall OR time

Laparoscopic• shorter hospital stay• equal OR time to open group

ResultsResultsAntibody TestingAntibody Testing

Investigational•rhBMP-2 antibodies

– 1 patient positive = overall failure

•Antibovine type I collagen antibodies

– 18 positives– 15 overall success

•Human Type I collagen– no positives

Control•rhBMP-2 antibodies

– 1 patient positive = overall success

•Antibovine type I collagen antibodies

– 16 positives – 10 overall success

•Human Type I collagen– no positives


Laparoscopic•rhBMP-2 antibodies

– 1 patient positive = overall failure

•antibovine type I collagen antibodies

– 32 positives

– 17 overall success

•human Type I collagen– no positives


• No correlation of antibody results with overall or individual success or failure

• No correlation of antibody results with the occurrence of adverse events

ResultsResultsOther Effectiveness EndpointsOther Effectiveness Endpoints

for both groups:

• return to work ~ 64 days• laparoscopic patients returned 20 days

faster

ConclusionsConclusionsPrimary Effectiveness EndpointsPrimary Effectiveness Endpoints

equivalent to control?Fusion YesOswestry score YesNeuro status YesOverall success Yes

ConclusionsConclusionsSecondary Effectiveness Secondary Effectiveness

EndpointsEndpoints

equivalent to control?back pain Noleg pain YesSF-36 PCS YesSF-36 MCS Nodisc height Yes

ResultsResultsAdverse EventsAdverse Events

• one death - control patient w/CAD• incidence of any adverse event in both

groups = 70-80%• 8 events related to donor site• 6 pregnancies, 2 Miscarriages

ResultsResultsAdverse Event Rates Adverse Event Rates

urogenital** retrograde

ejaculation ** graft site related*


• Retrograde ejaculation • higher investigational and laparoscopic

• urogenital• No immune-related adverse events• 2 cases of cancer- pancreatic, breast

• no osteogenic cancer


Investigational Control Laparoscopic

devicerelated

17(11.9%)

11(13.2%)

13(9.7%)

surgeryrelated

117 106 103

seriousevents

11(7.7%)

10(8.3%)

5(3.7%)

Device Related EventsDevice Related Events

• No bent, broken devices

• Investigational > control• migration of devices

• malpositioned devices

• Control > Investigational• loosening/displacement • subsidence

• Investigational = Control• cysts found inferior to implant

Device Related EventsDevice Related Events

• Laparoscopic approach associated with higher incidence• device malposition• anatomic difficulties• retrograde ejaculation

ResultsResultsSecond SurgeriesSecond Surgeries

Investigational Control Laparoscopic

Revisions 0 0 1

Removals 2 0 2

SupplementalFixations 10 14 7

Clinical ConclusionsClinical Conclusions

• equivalent clinical effectiveness• equivalent safety

• similar second surgery rates• similar adverse event rates

• avoids donor site morbidity

Radiographic InterpretationRadiographic Interpretation


• X-rays

• thin slice CT and reconstructions


Xrays and CT scan Comparisons• Clinical Trial• Animal

• Autograft• BMP

• Human• Autograft• BMP

Radiographic successRadiographic successFusionFusion

• plain films: A/P, lateral, flex/ext

• CT scans: 1mm slices w/1mm index– evidence of bridging trabeculae– no lucency around > 50% of either cage– no motion

• < 3 mm translation on lateral F/E• < 5o angular motion on lateral F/E

Radiographic interpretationRadiographic interpretationXray vs. CT scanXray vs. CT scan

bridging bone – n (% patients)

time post-op(months)

methodOpen

(n = 143)Control(n = 136)

Lap(n = 134)

x-ray 38 (26.5) 21 (15.9) 15 (11.2)6

CT 128 (89.5) 114 (83.8) 84 (62.6)

x-ray 75 (52.4) 39 (28.7) 53 (39.6)12

CT 126 (88.1) 110 (80.9) 93 (69.4)

x-ray 111 (77.6) 97 (71.3) 81 (60.4)24

CT 117 (81.8) 99 (73.0) 78 (58.2)

6 month CT6 month CTSuccessSuccess

12 Month CT 12 Month CT SuccessSuccess

24 Month CT24 Month CTSuccessSuccess

6 Month CT6 Month CTFailureFailure

12 Month CT12 Month CT FailureFailure

24 Month CT24 Month CT FailureFailure

Radiographic interpretationRadiographic interpretationX-ray vs. CT scanX-ray vs. CT scan

Conclusions from comparative studies: AUTOGRAFT

• X-rays and CT compared to surgical exploration, manipulation, histology: Animal and Human

• CT scans (reconstructions) correlated with manipulation, histology

• CT scans higher sensitivity and specificity

Radiographic interpretationRadiographic interpretationX-ray vs. CT scanX-ray vs. CT scan

Conclusions from comparative studies: rhBMP-2

• X-rays and CT compared to surgical exploration, manipulation, histology: animal studies

• CT scans (reconstructions) correlated with manipulation, histology

• Appearance (density), and rate of progression differ from autograft and allograft

Radiographic InterpretationRadiographic InterpretationXrays vs. CT scansXrays vs. CT scans

Considerations:• High fusion rates using both Xray and CT

in human clinical trial

• Xray/CT validation based on Autograft• may not be able to extrapolate animal data to

potential human responses• rate and extent of radiographic changes between

auto graft and rhBMP/ACS differ

Radiographic Interpretation Radiographic Interpretation Issues to considerIssues to consider

• Presence and absorption rate of the collagen sponge

• identification of the progression of the bone repair process in the presence of rhBMP-2

• ability of bone formed at various time points to accommodate applied loads

• implications on the interpretation of radiographic fusion and physician training

Documents

Clinical Review Barbara Buch, M.D. Orthopaedic Surgeon FDA Orthopaedic Devices Branch