Validation of Onyx Response Computational Assessment (ORCA) Against Blinded Independent Review Committee (IRC) for the Determination of Progression in Multiple Myeloma Trials

• Activity Number: 192
• Type: Contributed
• Date/Time: Monday, August 10, 2015 : 10:30 AM to 12:20 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Zhiwu Yan* and Sunhee Ro
• Companies: Onyx Pharmaceuticals and Onyx Pharmaceuticals
• Keywords: multiple myeloma ; IMWG-URC ; PFS ; IRC ; dEDR ; dLDR

Abstract

In multiple myeloma, the IMWG Uniform Response Criteria (IMWG-URC) are widely used for the determination of response and progression and are mostly based on changes of para-protein in serum and urine which can be centrally measured in a clinical trial. Therefore it is feasible for us to develop ORCA, a computer-based tool based on IMWG-URC for the blinded and objective determination of progression-free survival (PFS) especially in open label trials where investigators' assessments may be biased. We compared ORCA-based PFS results with IRC's (considered gold standard) using the method of Amit et al (2011) based on an independent phase 3 study and investigated the performance of the two metrics suggested in the paper, differential early discrepancy rate (dEDR), and late discrepancy rate (dLDR), using both actual and simulated datasets. Our results show that PFS by ORCA can be a successful surrogate for PFS by IRC. We noted limitations of using dLDR as a validation metric when the observed concordance is high. Simulation results based on the method of Korn et al (2010) to assess the impact of measurement errors in ORCA-based PFS on the hazard ratio estimation will also be presented.