clinical review barbara buch, m.d. orthopaedic surgeon fda orthopaedic devices branch
TRANSCRIPT
Clinical ReviewClinical Review
Barbara Buch, M.D.
Orthopaedic Surgeon
FDA Orthopaedic Devices Branch
Clinical ReviewClinical Review
• 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
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
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
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
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
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*
ResultsResultsAdverse EventsAdverse Events
• Retrograde ejaculation • higher investigational and laparoscopic
• urogenital• No immune-related adverse events• 2 cases of cancer- pancreatic, breast
• no osteogenic cancer
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%)
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
Radiographic InterpretationRadiographic Interpretation
• X-rays
• thin slice CT and reconstructions
Radiographic InterpretationRadiographic Interpretation
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