1. International Randomized Trials in Orthopaedic Oncology: Joining Forces and Shifting the Paradigm Michelle Ghert, MD, FRCSC Center for Evidence-Based Orthopaedics McMaster University

3. Disclosure Committee Chair: Orthopaedic Research Society Committee Member: Musculoskeletal Tumor Society Grand Funding: OREF, MSTS, PSI, CCSRI, MSA Private Funding: Manherz Family Donation

4. Overview Learning Process Take Home Points:  Trials require:1. The right question 2. Centralized infrastructure 3. Collaborative network

5. Where the Process Started

6. Strong Pull to 'The Dark Side’

7. First ever Department of Clinical Epidemiology Chairman: Dr. David Sackett Dr. David Sackett M.S. from Harvard Epidemiology Mentor Dr. Gordon Guyatt Coined the term “Evidence-Based Medicine” Mentor Dr. Mohit Bhandari Unparalleled transformation in orthopaedic research Prospective international randomized controlled trials Mentor

8. Clinical Epidemiology: Absorbed through osmosis

9. “Elephant in Paris” moment CTOS 2010

10. Will it work? Trials require:1. The right question 2. Centralized infrastructure 3. Collaborative network

11. Challenges to Prospective Research

12. Current Evidence in Orthopaedic Oncology

13. SPRINT Trial

14. SPRINT trial: 1339 patients, 95% follow-up FLOW trial: 2500 patients recruited, target 2520 FAITH trial: 990 patients, target 1000 TRUST trial: 500 patients, target 1000 HEALTH trial: 358 patients, target 1400 INORMUS and PRAISE cohorts: 7900 patients Collaboration with over 150 centers around the world

15. Preliminary Steps for a Surgical Trial 1.Find an important question 2.Systematic review 3.Survey the field 4.Publish a protocol 5.Apply for funding

16. 22 year-old male with sarcoma right femur

24. 58year-old female

28. Clinical Question: PICO Population Intervention Comparison Outcome

29. Preliminary Steps for a Surgical Trial 1.Find a question important to your field 2.Systematic review 3.Survey the field for practice and opinion 4.Publish a protocol 5.Apply for funding

32. Preliminary Steps for a Surgical Trial 1.Find an important question 2.Systematic review 3.Survey the field 4.Publish a protocol 5.Apply for funding

34. Length of Time Prophylactic Antibiotics Prescribed Following Long-bone Reconstruction Type of Reconstruction24 hrs48 hrs3-7 daysUntil Suction Drain Removed Tumor prosthesis 25 (35.7%) 13 (18.6%) 3 (4.3%)29 (41.4%) Allograft 18 (26.5%) 13 (19.1%) 11 (16.2%) 26 (38.2%) Allograft-prosthesis composite 17 (25.4%) 12 (17.9%) 9 (13.4%)29 (43.3%)

36. Preliminary Steps for a Surgical Trial 1.Find an important question 2.Systematic review 3.Survey the field 4.Publish a protocol 5.Apply for funding

37. Patient screened and eligible and provides informed consent Randomization Standard pre-op and intra-op antibiotics AND 24 hours post op antibiotics Standard pre-op and intra-op antibiotics AND 5 days post op antibiotics Follow-up one year Study Design

40. Sample Size Calculation Infection rate: 10% Superiority of long-term antibiotics: –threshold of 5% for inferiority Estimated sample size of 920

42. Preliminary Steps for a Surgical Trial 1.Find an important question 2.Systematic review 3.Survey the field 4.Publish a protocol 5.Apply for funding

43. Writing Grants

44. Research Funding: Pilot (vanguard phase)

45. What you need to run RCTs Trials require:1. The right question √ 2. Centralized infrastructure 3. Collaborative network

46. What you need to run RCTs Trials require:1. The right question √ 2. Centralized infrastructure 3. Collaborative network

47. Methods Center Nominated Principal Investigator Co-Investigators Senior Biostatistician Statistician Data Manager Study Coordinator Research Assistants Administrative Assistants Graduate Students

48. Central Source of Information

49. Newsletter and website

50. Budgeting and Contracts

51. STEERING COMMITTEE Overall responsibility for the trial CENTRAL ADJUDICATION COMMITTEE Review and classification of all clinical events DATA MONITORING COMMITTEE Review of adverse events and stopping rules based on benefit and harm METHODS AND COORDINATING CENTRE Data management, daily conduct of the trial PARTICIPATING CLINICAL CENTRES Patient recruitment and follow-up as per study protocol PARITY Trial Organization

56. Adjudication

57. Methods Center Personnel Nominated Principal Investigator Co-Investigators Senior Biostatistician Statistician Data Manager Study Coordinator Research Assistants Grants Administrator Graduate Students

58. Principal Investigator Nominated Principal Investigator Co-Investigators Senior Biostatistician Statistician Data Manager Study Coordinator Research Assistants Grants Administrator Graduate Students

59. Co-Investigators, Senior Biostatistician Nominated Principal Investigator Co-Investigators Senior Biostatistician Statistician Data Manager Study Coordinator Research Assistants Grants Administrator Graduate Students

60. Study Coordinator Nominated Principal Investigator Co-Investigators Senior Biostatistician Statistician Data Manager Study Coordinator Research Assistants Grants Administrator Graduate Students

61. Statistician Nominated Principal Investigator Co-Investigators Senior Biostatistician Statistician Data Manager Study Coordinator Research Assistants Grants Administrator Graduate Students

62. Data Manager Nominated Principal Investigator Co-Investigators Senior Biostatistician Statistician Data Manager Study Coordinator Research Assistants Grants Administrator Graduate Students

63. Nominated Principal Investigator Co-Investigators Senior Biostatistician Statistician Data Manager Study Coordinator Research Assistants Grants Administrator Graduate Students

64. Research Assistants Nominated Principal Investigator Co-Investigators Senior Biostatistician Statistician Data Manager Study Coordinator Research Assistants Grants Administrator Graduate Students

65. Grants Administrator Nominated Principal Investigator Co-Investigators Senior Biostatistician Statistician Data Manager Study Coordinator Research Assistants Grants Administrator Graduate Students

66. What you need to run RCTs Trials require:1. The right question √ 2. Centralized infrastructure √ 3. Collaborative network

67. What you need to run RCTs Trials require:1. The right question √ 2. Centralized infrastructure √ 3. Collaborative network

70. STEERING COMMITTEE Overall responsibility for the trial CENTRAL ADJUDICATION COMMITTEE Review and classification of all clinical events DATA MONITORING COMMITTEE Review of adverse events and stopping rules based on benefit and harm METHODS AND COORDINATING CENTRE Data management, daily conduct of the trial PARTICIPATING CLINICAL CENTRES Patient recruitment and follow-up as per study protocol PARITY Trial Organization

71. International PARITY Sites

72. PARITY Investigators Michelle Ghert, Benjamin Deheshi, Gita Sobhi, Peter Ferguson, Jay Wunder, Robert Turcotte, Joel Werier, Paul Clarkson, Marc Isler, R. Lor Randall, Ginger Holt, Megan Anderson, John Healey, Marcos Galli, Rob Grimer, Tom Scharschmidt, Ed Chang, Benjamin Miler, Norbert Dion, Sevan Hopyan, Rob Pollock, Graig Gerrand, William Aston, Max Gibbons, John Abraham, Tessa Balach, Paul Cool. Minna Laitinen, Yair Gortzak, Yoshihiro Nishida, Tabu Gokita, Doran Frantzen, Leonard Marais, Matthew DiCaprio, Felix Cheung, Howard Rosenthal, Ernest Conrad, Timothy Damron, Joseph Benevenia, Mark Gebhardt, Sophie Mottard, Nathan Evaniew, Antonella Racano, Sheila Sprague, Marilyn Swinton, Dianne Bryant, Lehana Thabane, Gordon Guyatt, Mohit Bhandari

74. Paradigm shift from Level IV to Level I Evidence

75. Take Home Points Trials require:1. The right question 2. Centralized infrastructure 3. Collaborative network Collaboration is the foundation of RCTs, without which the endeavour will collapse

76. Thank-you