clinical review barbara buch, m.d. orthopaedic surgeon fda orthopaedic devices branch
TRANSCRIPT
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Clinical ReviewClinical Review
Barbara Buch, M.D.
Orthopaedic Surgeon
FDA Orthopaedic Devices Branch
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Clinical ReviewClinical Review
• Clinical Summary• Highlights of Effectiveness and Safety
• Radiographic Interpretation: Summary of Additional information
• Radiographic Interpretation: Considerations for Panel Discussion
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Clinical SummaryClinical Summary
• prospective• randomized• multi-center• concurrently controlled• independent radiologists• Bayesian statistical analysis• high patient & data accountability• meticulous adverse event reporting
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Clinical ReviewClinical Review
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
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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
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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
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ResultsResultsEquivalent FindingsEquivalent Findings
• demographics
• co-morbidity
• pre-op medical conditions
• diagnostic factors
• levels treated
• use of post-op bracing
• pre-op evaluations
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ResultsResultsIntraoperativeIntraoperative
Investigational group• less EBL• less overall OR time
Laparoscopic• shorter hospital stay• equal OR time to open group
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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
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ResultsResultsAntibody TestingAntibody Testing
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
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ResultsResultsAntibody TestingAntibody Testing
• No correlation of antibody results with overall or individual success or failure
• No correlation of antibody results with the occurrence of adverse events
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ResultsResultsOther Effectiveness EndpointsOther Effectiveness Endpoints
for both groups:
• return to work ~ 64 days• laparoscopic patients returned 20 days
faster
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ConclusionsConclusionsPrimary Effectiveness EndpointsPrimary Effectiveness Endpoints
equivalent to control?Fusion YesOswestry score YesNeuro status YesOverall success Yes
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ConclusionsConclusionsSecondary Effectiveness Secondary Effectiveness
EndpointsEndpoints
equivalent to control?back pain Noleg pain YesSF-36 PCS YesSF-36 MCS Nodisc height Yes
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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
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ResultsResultsAdverse Event Rates Adverse Event Rates
urogenital** retrograde
ejaculation ** graft site related*
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ResultsResultsAdverse EventsAdverse Events
• Retrograde ejaculation • higher investigational and laparoscopic
• urogenital• No immune-related adverse events• 2 cases of cancer- pancreatic, breast
• no osteogenic cancer
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ResultsResultsAdverse EventsAdverse Events
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%)
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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
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Device Related EventsDevice Related Events
• Laparoscopic approach associated with higher incidence• device malposition• anatomic difficulties• retrograde ejaculation
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ResultsResultsSecond SurgeriesSecond Surgeries
Investigational Control Laparoscopic
Revisions 0 0 1
Removals 2 0 2
SupplementalFixations 10 14 7
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Clinical ConclusionsClinical Conclusions
• equivalent clinical effectiveness• equivalent safety
• similar second surgery rates• similar adverse event rates
• avoids donor site morbidity
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Radiographic InterpretationRadiographic Interpretation
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Radiographic InterpretationRadiographic Interpretation
• X-rays
• thin slice CT and reconstructions
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Radiographic InterpretationRadiographic Interpretation
Xrays and CT scan Comparisons• Clinical Trial• Animal
• Autograft• BMP
• Human• Autograft• BMP
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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
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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)
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6 month CT6 month CTSuccessSuccess
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12 Month CT 12 Month CT SuccessSuccess
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24 Month CT24 Month CTSuccessSuccess
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6 Month CT6 Month CTFailureFailure
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12 Month CT12 Month CT FailureFailure
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24 Month CT24 Month CT FailureFailure
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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
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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
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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
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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