International Randomized Trials in Orthopaedic Oncology:

Joining Forces and Shifting the Paradigm

Michelle Ghert, MD, FRCSCCenter for Evidence-Based

OrthopaedicsMcMaster University

Disclosure

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

Overview

• Learning Process• Take Home Points:

Trials require: 1. The right question2. Centralized

infrastructure3. Collaborative network

Where the Process Started

Strong Pull to 'The Dark Side’

First ever Department of Clinical Epidemiology Chairman: Dr. David Sackett

Dr. David SackettM.S. from Harvard Epidemiology

Mentor

Dr. Gordon GuyattCoined the term “Evidence-Based Medicine”

Mentor

Dr. Mohit BhandariUnparalleled transformation in orthopaedic researchProspective international randomized controlled trials

Mentor

Clinical Epidemiology: Absorbed through osmosis

“Elephant in Paris” moment

CTOS 2010

Will it work?

• Trials require: 1. The right question2. Centralized infrastructure3. Collaborative network

Challenges to Prospective Research

Current Evidence in Orthopaedic Oncology

SPRINT Trial

Favours Reamed Favours Unreamed1 5 100.5

Event Rate, % Relative Risk (95% CI)

50 Patients 20.0 2.65 (0.59, 11.86)

100 Patients 24.3 2.14 (0.84, 5.43)

200 Patients 18.1 1.08 (0.53, 2.20)

300 Patients 18.1 1.04 (0.58, 1.85)

400 Patients 18.4 1.07 (0.65, 1.76)

500 Patients 17.2 0.92 (0.58, 1.47)

600 Patients 15.8 0.81 (0.51, 1.26)

700 Patients 15.3 0.73 (0.48, 1.12)

800 Patients 14.7 0.65 (0.43, 0.99)

900 Patients 14.7 0.57 (0.40, 0.87)

1000 Patients 14.1 0.63 (0.43, 0.91)

1100 Patients 14.0 0.66 (0.46, 0.94)

1226 Patients 13.7 0.65 (0.46, 0.93)

Favours Reamed Favours Unreamed1 5 100.5

Event Rate, % Relative Risk (95% CI)

50 Patients 20.0 2.65 (0.59, 11.86)

100 Patients 24.3 2.14 (0.84, 5.43)

200 Patients 18.1 1.08 (0.53, 2.20)

300 Patients 18.1 1.04 (0.58, 1.85)

400 Patients 18.4 1.07 (0.65, 1.76)

500 Patients 17.2 0.92 (0.58, 1.47)

600 Patients 15.8 0.81 (0.51, 1.26)

700 Patients 15.3 0.73 (0.48, 1.12)

800 Patients 14.7 0.65 (0.43, 0.99)

900 Patients 14.7 0.57 (0.40, 0.87)

1000 Patients 14.1 0.63 (0.43, 0.91)

1100 Patients 14.0 0.66 (0.46, 0.94)

1226 Patients 13.7 0.65 (0.46, 0.93)

Favours Reamed Favours Unreamed1 5 100.5

Event Rate, % Relative Risk (95% CI)

50 Patients 20.0 2.65 (0.59, 11.86)

100 Patients 24.3 2.14 (0.84, 5.43)

200 Patients 18.1 1.08 (0.53, 2.20)

300 Patients 18.1 1.04 (0.58, 1.85)

400 Patients 18.4 1.07 (0.65, 1.76)

500 Patients 17.2 0.92 (0.58, 1.47)

600 Patients 15.8 0.81 (0.51, 1.26)

700 Patients 15.3 0.73 (0.48, 1.12)

800 Patients 14.7 0.65 (0.43, 0.99)

900 Patients 14.7 0.57 (0.40, 0.87)

1000 Patients 14.1 0.63 (0.43, 0.91)

1100 Patients 14.0 0.66 (0.46, 0.94)

1226 Patients 13.7 0.65 (0.46, 0.93)

Favours Reamed Favours Unreamed1 5 100.5

Event Rate, % Relative Risk (95% CI)

50 Patients 20.0 2.65 (0.59, 11.86)

100 Patients 24.3 2.14 (0.84, 5.43)

200 Patients 18.1 1.08 (0.53, 2.20)

300 Patients 18.1 1.04 (0.58, 1.85)

400 Patients 18.4 1.07 (0.65, 1.76)

500 Patients 17.2 0.92 (0.58, 1.47)

600 Patients 15.8 0.81 (0.51, 1.26)

700 Patients 15.3 0.73 (0.48, 1.12)

800 Patients 14.7 0.65 (0.43, 0.99)

900 Patients 14.7 0.57 (0.40, 0.87)

1000 Patients 14.1 0.63 (0.43, 0.91)

1100 Patients 14.0 0.66 (0.46, 0.94)

1226 Patients 13.7 0.65 (0.46, 0.93)

Favours Reamed Favours Unreamed1 5 100.5

Event Rate, % Relative Risk (95% CI)

50 Patients 20.0 2.65 (0.59, 11.86)

100 Patients 24.3 2.14 (0.84, 5.43)

200 Patients 18.1 1.08 (0.53, 2.20)

300 Patients 18.1 1.04 (0.58, 1.85)

400 Patients 18.4 1.07 (0.65, 1.76)

500 Patients 17.2 0.92 (0.58, 1.47)

600 Patients 15.8 0.81 (0.51, 1.26)

700 Patients 15.3 0.73 (0.48, 1.12)

800 Patients 14.7 0.65 (0.43, 0.99)

900 Patients 14.7 0.57 (0.40, 0.87)

1000 Patients 14.1 0.63 (0.43, 0.91)

1100 Patients 14.0 0.66 (0.46, 0.94)

1226 Patients 13.7 0.65 (0.46, 0.93)

Favours Reamed Favours Unreamed1 5 100.5

Event Rate, % Relative Risk (95% CI)

50 Patients 20.0 2.65 (0.59, 11.86)

100 Patients 24.3 2.14 (0.84, 5.43)

200 Patients 18.1 1.08 (0.53, 2.20)

300 Patients 18.1 1.04 (0.58, 1.85)

400 Patients 18.4 1.07 (0.65, 1.76)

500 Patients 17.2 0.92 (0.58, 1.47)

600 Patients 15.8 0.81 (0.51, 1.26)

700 Patients 15.3 0.73 (0.48, 1.12)

800 Patients 14.7 0.65 (0.43, 0.99)

900 Patients 14.7 0.57 (0.40, 0.87)

1000 Patients 14.1 0.63 (0.43, 0.91)

1100 Patients 14.0 0.66 (0.46, 0.94)

1226 Patients 13.7 0.65 (0.46, 0.93)

Favours Reamed Favours Unreamed1 5 100.5

Event Rate, % Relative Risk (95% CI)

50 Patients 20.0 2.65 (0.59, 11.86)

100 Patients 24.3 2.14 (0.84, 5.43)

200 Patients 18.1 1.08 (0.53, 2.20)

300 Patients 18.1 1.04 (0.58, 1.85)

400 Patients 18.4 1.07 (0.65, 1.76)

500 Patients 17.2 0.92 (0.58, 1.47)

600 Patients 15.8 0.81 (0.51, 1.26)

700 Patients 15.3 0.73 (0.48, 1.12)

800 Patients 14.7 0.65 (0.43, 0.99)

900 Patients 14.7 0.57 (0.40, 0.87)

1000 Patients 14.1 0.63 (0.43, 0.91)

1100 Patients 14.0 0.66 (0.46, 0.94)

1226 Patients 13.7 0.65 (0.46, 0.93)

Favours Reamed Favours Unreamed1 5 100.5

Event Rate, % Relative Risk (95% CI)

50 Patients 20.0 2.65 (0.59, 11.86)

100 Patients 24.3 2.14 (0.84, 5.43)

200 Patients 18.1 1.08 (0.53, 2.20)

300 Patients 18.1 1.04 (0.58, 1.85)

400 Patients 18.4 1.07 (0.65, 1.76)

500 Patients 17.2 0.92 (0.58, 1.47)

600 Patients 15.8 0.81 (0.51, 1.26)

700 Patients 15.3 0.73 (0.48, 1.12)

800 Patients 14.7 0.65 (0.43, 0.99)

900 Patients 14.7 0.57 (0.40, 0.87)

1000 Patients 14.1 0.63 (0.43, 0.91)

1100 Patients 14.0 0.66 (0.46, 0.94)

1226 Patients 13.7 0.65 (0.46, 0.93)

Favours Reamed Favours Unreamed1 5 100.5

Event Rate, % Relative Risk (95% CI)

50 Patients 20.0 2.65 (0.59, 11.86)

100 Patients 24.3 2.14 (0.84, 5.43)

200 Patients 18.1 1.08 (0.53, 2.20)

300 Patients 18.1 1.04 (0.58, 1.85)

400 Patients 18.4 1.07 (0.65, 1.76)

500 Patients 17.2 0.92 (0.58, 1.47)

600 Patients 15.8 0.81 (0.51, 1.26)

700 Patients 15.3 0.73 (0.48, 1.12)

800 Patients 14.7 0.65 (0.43, 0.99)

900 Patients 14.7 0.57 (0.40, 0.87)

1000 Patients 14.1 0.63 (0.43, 0.91)

1100 Patients 14.0 0.66 (0.46, 0.94)

1226 Patients 13.7 0.65 (0.46, 0.93)

Favours Reamed Favours Unreamed1 5 100.5

Event Rate, % Relative Risk (95% CI)

50 Patients 20.0 2.65 (0.59, 11.86)

100 Patients 24.3 2.14 (0.84, 5.43)

200 Patients 18.1 1.08 (0.53, 2.20)

300 Patients 18.1 1.04 (0.58, 1.85)

400 Patients 18.4 1.07 (0.65, 1.76)

500 Patients 17.2 0.92 (0.58, 1.47)

600 Patients 15.8 0.81 (0.51, 1.26)

700 Patients 15.3 0.73 (0.48, 1.12)

800 Patients 14.7 0.65 (0.43, 0.99)

900 Patients 14.7 0.57 (0.40, 0.87)

1000 Patients 14.1 0.63 (0.43, 0.91)

1100 Patients 14.0 0.66 (0.46, 0.94)

1226 Patients 13.7 0.65 (0.46, 0.93)

Favours Reamed Favours Unreamed1 5 100.5

Event Rate, % Relative Risk (95% CI)

50 Patients 20.0 2.65 (0.59, 11.86)

100 Patients 24.3 2.14 (0.84, 5.43)

200 Patients 18.1 1.08 (0.53, 2.20)

300 Patients 18.1 1.04 (0.58, 1.85)

400 Patients 18.4 1.07 (0.65, 1.76)

500 Patients 17.2 0.92 (0.58, 1.47)

600 Patients 15.8 0.81 (0.51, 1.26)

700 Patients 15.3 0.73 (0.48, 1.12)

800 Patients 14.7 0.65 (0.43, 0.99)

900 Patients 14.7 0.57 (0.40, 0.87)

1000 Patients 14.1 0.63 (0.43, 0.91)

1100 Patients 14.0 0.66 (0.46, 0.94)

1226 Patients 13.7 0.65 (0.46, 0.93)

Favours Reamed Favours Unreamed1 5 100.5

Event Rate, % Relative Risk (95% CI)

50 Patients 20.0 2.65 (0.59, 11.86)

100 Patients 24.3 2.14 (0.84, 5.43)

200 Patients 18.1 1.08 (0.53, 2.20)

300 Patients 18.1 1.04 (0.58, 1.85)

400 Patients 18.4 1.07 (0.65, 1.76)

500 Patients 17.2 0.92 (0.58, 1.47)

600 Patients 15.8 0.81 (0.51, 1.26)

700 Patients 15.3 0.73 (0.48, 1.12)

800 Patients 14.7 0.65 (0.43, 0.99)

900 Patients 14.7 0.57 (0.40, 0.87)

1000 Patients 14.1 0.63 (0.43, 0.91)

1100 Patients 14.0 0.66 (0.46, 0.94)

1226 Patients 13.7 0.65 (0.46, 0.93)

Favours Reamed Favours Unreamed1 5 100.5

Event Rate, % Relative Risk (95% CI)

50 Patients 20.0 2.65 (0.59, 11.86)

100 Patients 24.3 2.14 (0.84, 5.43)

200 Patients 18.1 1.08 (0.53, 2.20)

300 Patients 18.1 1.04 (0.58, 1.85)

400 Patients 18.4 1.07 (0.65, 1.76)

500 Patients 17.2 0.92 (0.58, 1.47)

600 Patients 15.8 0.81 (0.51, 1.26)

700 Patients 15.3 0.73 (0.48, 1.12)

800 Patients 14.7 0.65 (0.43, 0.99)

900 Patients 14.7 0.57 (0.40, 0.87)

1000 Patients 14.1 0.63 (0.43, 0.91)

1100 Patients 14.0 0.66 (0.46, 0.94)

1226 Patients 13.7 0.65 (0.46, 0.93)

Favours Reamed Favours Unreamed1 5 100.5

Event Rate, % Relative Risk (95% CI)

50 Patients 20.0 2.65 (0.59, 11.86)

100 Patients 24.3 2.14 (0.84, 5.43)

200 Patients 18.1 1.08 (0.53, 2.20)

300 Patients 18.1 1.04 (0.58, 1.85)

400 Patients 18.4 1.07 (0.65, 1.76)

500 Patients 17.2 0.92 (0.58, 1.47)

600 Patients 15.8 0.81 (0.51, 1.26)

700 Patients 15.3 0.73 (0.48, 1.12)

800 Patients 14.7 0.65 (0.43, 0.99)

900 Patients 14.7 0.57 (0.40, 0.87)

1000 Patients 14.1 0.63 (0.43, 0.91)

1100 Patients 14.0 0.66 (0.46, 0.94)

1226 Patients 13.7 0.65 (0.46, 0.93)

Favours Reamed Favours Unreamed1 5 100.5

Event Rate, % Relative Risk (95% CI)

50 Patients 20.0 2.65 (0.59, 11.86)

100 Patients 24.3 2.14 (0.84, 5.43)

200 Patients 18.1 1.08 (0.53, 2.20)

300 Patients 18.1 1.04 (0.58, 1.85)

400 Patients 18.4 1.07 (0.65, 1.76)

500 Patients 17.2 0.92 (0.58, 1.47)

600 Patients 15.8 0.81 (0.51, 1.26)

700 Patients 15.3 0.73 (0.48, 1.12)

800 Patients 14.7 0.65 (0.43, 0.99)

900 Patients 14.7 0.57 (0.40, 0.87)

1000 Patients 14.1 0.63 (0.43, 0.91)

1100 Patients 14.0 0.66 (0.46, 0.94)

1226 Patients 13.7 0.65 (0.46, 0.93)

• 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

Preliminary Steps for a Surgical Trial

1. Find an important question2. Systematic review3. Survey the field4. Publish a protocol5. Apply for funding

22 year-old male with sarcoma right femur

58year-old female

Clinical Question: PICO

PopulationInterventionComparisonOutcome

Preliminary Steps for a Surgical Trial

1. Find a question important to your field2. Systematic review3. Survey the field for practice and opinion4. Publish a protocol5. Apply for funding

Preliminary Steps for a Surgical Trial

1. Find an important question2. Systematic review3. Survey the field4. Publish a protocol5. Apply for funding

Length of Time Prophylactic Antibiotics Prescribed Following Long-bone Reconstruction

Type of Reconstruction 24 hrs 48 hrs 3-7 days Until 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%)

Preliminary Steps for a Surgical Trial

1. Find an important question2. Systematic review3. Survey the field4. Publish a protocol5. Apply for funding

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

Follow-up one year

Study Design

Sample Size Calculation

• Infection rate: 10%• Superiority of long-term antibiotics:

– threshold of 5% for inferiority• Estimated sample size of 920

Preliminary Steps for a Surgical Trial

1. Find an important question2. Systematic review3. Survey the field4. Publish a protocol5. Apply for funding

Writing Grants

Research Funding: Pilot (vanguard phase)

What you need to run RCTs

• Trials require: 1. The right question √2. Centralized infrastructure3. Collaborative network

What you need to run RCTs

• Trials require: 1. The right question √2. Centralized infrastructure3. Collaborative network

Methods Center

Nominated Principal Investigator

Co-InvestigatorsSenior Biostatistician

Statistician

Data Manager

Study Coordinator

Research Assistants

Administrative Assistants

Graduate Students

Central Source of Information

Newsletter and website

Budgeting and Contracts

STEERING COMMITTEEOverall 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

Adjudication

Methods Center Personnel

Nominated Principal Investigator

Co-InvestigatorsSenior Biostatistician

Statistician

Data Manager

Study Coordinator

Research Assistants

Grants Administrator

Graduate Students

Principal Investigator

Nominated Principal Investigator

Co-InvestigatorsSenior Biostatistician

Statistician

Data Manager

Study Coordinator

Research Assistants

Grants Administrator

Graduate Students

Co-Investigators, Senior Biostatistician

Nominated Principal Investigator

Co-InvestigatorsSenior Biostatistician

Statistician

Data Manager

Study Coordinator

Research Assistants

Grants Administrator

Graduate Students

Study Coordinator

Nominated Principal Investigator

Co-InvestigatorsSenior Biostatistician

Statistician

Data Manager

Study Coordinator

Research Assistants

Grants Administrator

Graduate Students

Statistician

Nominated Principal Investigator

Co-InvestigatorsSenior Biostatistician

Statistician

Data Manager

Study Coordinator

Research Assistants

Grants Administrator

Graduate Students

Data Manager

Nominated Principal Investigator

Co-InvestigatorsSenior Biostatistician

Statistician

Data Manager

Study Coordinator

Research Assistants

Grants Administrator

Graduate Students

Graduate Students

Nominated Principal Investigator

Co-InvestigatorsSenior Biostatistician

Statistician

Data Manager

Study Coordinator

Research Assistants

Grants Administrator

Graduate Students

Research Assistants

Nominated Principal Investigator

Co-InvestigatorsSenior Biostatistician

Statistician

Data Manager

Study Coordinator

Research Assistants

Grants Administrator

Graduate Students

Grants Administrator

Nominated Principal Investigator

Co-InvestigatorsSenior Biostatistician

Statistician

Data Manager

Study Coordinator

Research Assistants

Grants Administrator

Graduate Students

What you need to run RCTs

• Trials require: 1. The right question √2. Centralized infrastructure √3. Collaborative network

What you need to run RCTs

• Trials require: 1. The right question √2. Centralized infrastructure √3. Collaborative network

STEERING COMMITTEEOverall 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

International PARITY Sites

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

Dec '12 Jan '13 Feb Mar Apr May Jun Jul

0

5

10

15

20

25

30

35

Cumulative Enrollment

Paradigm shift from Level IV to Level I Evidence

Take Home Points

• Trials require: 1. The right question2. Centralized infrastructure3. Collaborative network

• Collaboration is the foundation of RCTs, without which the endeavour will collapse

Thank-you