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

2. Clinical Review Clinical Summary Highlights of Effectiveness and Safety Radiographic Interpretation: Summary of Additional information Radiographic Interpretation: Considerations for Panel Discussion

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

4. Clinical Review

5. Clinical 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

6. Accountability at 24 months Randomized Patients patient 87 - 91% data –primary endpoints 90-95% –secondary endpoints > 89% antibody testing > 91% all groups

7. Results Equivalent Findings demographics co-morbidity pre-op medical conditions diagnostic factors levels treated use of post-op bracing pre-op evaluations

8. Results Intraoperative Investigational group less EBL less overall OR time Laparoscopic shorter hospital stay equal OR time to open group

9. Results Antibody 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

10. Results Antibody 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

11. Results Antibody Testing No correlation of antibody results with overall or individual success or failure No correlation of antibody results with the occurrence of adverse events

12. Results Other Effectiveness Endpoints for both groups: return to work ~ 64 days laparoscopic patients returned 20 days faster

13. Conclusions Primary Effectiveness Endpoints

14. Conclusions Secondary Effectiveness Endpoints

15. Results Adverse 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

16. Results Adverse Event Rates

17. Results Adverse Events Retrograde ejaculation higher investigational and laparoscopic urogenital No immune-related adverse events 2 cases of cancer- pancreatic, breast no osteogenic cancer

18. Results Adverse Events

19. Device 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

20. Device Related Events Laparoscopic approach associated with higher incidence device malposition anatomic difficulties retrograde ejaculation

21. Results Second Surgeries

22. Clinical Conclusions equivalent clinical effectiveness equivalent safety similar second surgery rates similar adverse event rates avoids donor site morbidity

23. Radiographic Interpretation

24. X-rays thin slice CT and reconstructions

25. Radiographic Interpretation Xrays and CT scan Comparisons Clinical Trial Animal Autograft BMP Human Autograft BMP

26. Radiographic success Fusion 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 < 5 o angular motion on lateral F/E

27. Radiographic interpretation Xray vs. CT scan

28. 6 month CT Success

29. 12 Month CT Success

30. 24 Month CT Success

31. 6 Month CT Failure

32. 12 Month CT Failure

33. 24 Month CT Failure

34. Radiographic interpretation X-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

35. Radiographic interpretation X-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

36. Radiographic Interpretation Xrays 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

37. Radiographic Interpretation Issues 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