rhBMP-2 soaked Absorbable Collagen Sponge (ACS) for the treatment of Open Tibial Shaft Fractures Clinical Summary

1. rhBMP-2 soaked Absorbable Collagen Sponge (ACS) for the treatment of Open Tibial Shaft Fractures Clinical Summary Points to consider

2. Clinical Summary of International Investigation

3. Clinical Review • Study Design • Effectiveness • Safety

4. Clinical Review • STUDY DESIGN • Confounding Variables • Patient Assessment • Study Endpoints • Data Analysis

5. Confounding Variables • Technique for IM nail insertion • All fracture types considered equal • Isolated fractures grouped with multiple injuries • Gustilo I ≠ Gustilo II ≠ Gustilo IIIA • Not all patients received a full sponge to the fracture site • Large centers ≠ small centers

6. Distribution of Patients by Country

7. Clinical Aspects of Pooling • Multiple centers • Over 50% of patients from 2 countries • Different experiences: • Few patients from many sites pooled with many patients from few sites • Different philosophies regarding optimal treatment : reamed vs. unreamed nails • Different interpretations of healing, delayed healing • Cultural and Geographic differences • Applicability to US trauma populations

8. Assessment Methods • Clinical • Fracture site tenderness • Radiographic union • Weight bearing status • Independent Radiographic

9. Patient Assessment • PAIN • No scale used for comparison • Differentiation between fracture sitetenderness and soft tissue injury difficult

11. Criteria For Radiographic Union for Independent Radiology Panel • A fracture was considered united when: • 3 of 4 cortices demonstrated cortical bridging and/or complete disappearance of fracture lines • This definition includes: • 3 of 4 cortices demonstrate bridging • 3 of 4 cortices demonstrated disappearance of fracture lines • 2 of 4 cortices demonstrate cortical bridging and at least 1 of the remaining 2 cortices demonstrate disappearance of fracture lines • 1 of 4 cortices demonstrated cortical bridging and at least 2 of the remaining 3 cortices demonstrated disappearance of fracture lines

13. Independent and Investigator Review • Gustillo Grade IIIA • Unreamed locked nail • 0.75 mg/ml rhBMP

15. Definitions • Healed Fracture: • Absence of tenderness upon manual palpation of the fracture site • Radiographic fracture union as assessed by the investigator • Full weight bearing status

16. Definitions • Delayed Union: • “A fracture is considered a delayed union if insufficient fracture healing was observed as determined by the investigators radiographic and clinical assessment”

17. Number of Patients with SI recommended & Patients meeting criteria of Delayed union

18. Primary Endpoint • Secondary Interventions : How was the decision made?

19. Study Design:Control Group • What is the standard of Care? • Depends on • Fracture type • Injury severity • Bone loss • Contamination • Concomitant injuries • Different prognoses for different types

20. Relevance of Endpoints • Primary Endpoint • Rate of Secondary Interventions • Recommended & Performed • Recommended & Not Performed • Not Recommended but Performed • Self Dynamizations (screw breakages) • Secondary Endpoints • Healing rate at 6 months • 50% probability of healing • CCRE

21. What is important? • How many healed? • What is the incidence of nonunion? • What are the complications and incidence? • Incidence of Infection? • Time to healing for majority of the patients?

22. Combined Clinical & Radiographic Endpoint (CCRE) • Independent review paired with investigator review • Clinical assessment compared to purely radiographic assessment • Patients with SI evaluated differently than patients without SI

23. Treatment of Missing Data • Inconsistent • Three examples

24. The Dilemma • Investigators unblinded • Investigators determined pain, weight bearing status and radiologic healing • Investigators determined when to perform secondary intervention • The CCRE is 50% dependent on investigators determination

25. The Dilemma • No time course/interval to delineate “delayed healing” from “healing” • No radiographic/clinical criteria to separate healing fracture vs. delayed healing • How patients with delayed healing fractures were recommended for secondary intervention is imprecise. • Extent to which all the investigators used the same criteria for determining a secondary intervention is unknown

26. Results • Effectiveness • Primary Endpoint • Rate of Fracture Healing • Time to event Analysis • Probability of 50% healing • Nonunion

27. Primary Endpoint

28. Rate of Fracture Healing

29. Probability of a Fracture Healing by Investigator

30. Time To Healing by Investigator

31. Time to Independent Radiographic Assessment of Fracture Union

32. Time to Fracture Healing by Independent Radiology Panel

33. Nonunion

34. Time to Fracture healing by Investigator Assessment : Patients with Secondary Interventions

35. Safety • Serology • Anti-rhBMP antibodies • Anti Type I Bovine collagen antibodies • Hardware failure • Laboratory Results • Heterotopic Ossification • Infection

36. Serology

37. Hardware Failure

38. Laboratory results • Liver function Tests elevated in rhBMP-2 treated groups • Elevated Amylase • Hypomagnesemia

39. Heterotopic Ossification

40. Infection Rate

41. CONCLUSIONS • Definitions for assessment unclear • Assessments based on investigators • Clinical relevance of endpoints • Control group as standard of care an issue • Pooling across different sites and applicability to US population an issue • Outcomes Interpretations differ • Safety questions