Number FRI0094

BLINDED READS IN RHEUMATOID ARTHRITIS CLINICAL TRIALS: ADJUDICATION RATES FOR VARYING THRESHOLDS BASED ON CHANGE SCORES OF TWO READERS UTILIZING X-RAYS OF THE HANDS AND FEET
2,000 Clinical Trials . International Clinical Trials . 11,000+ Site Managed . 80+Countries . Global . 27/4 Support . Site Training . Data Collection . Data Management . IVR Quality Control . Best-of-breed . Cardiology . Musculoskeletal . Osteoporosis . Osteoarthritis . Rheumatoid Arthritis . Oncology . Neurology . Efcacy . Diagnostic Agents . Clinical Trial Forecasting . Simulation . Buffer Stock Optimization . Clinical Trial Management . Imaging Core Lab . Therapeutic Expertise . Data Collection Expertise . Electronic Data Capture . Certied Radioloogist . Image Quality Control . Angiography . Phase I-IV . Clinical Data Management . FDA-compliant . Medical Image Management . CTMS Solutions . Innovative Technologies . Parameter Driven IWR . Global Delivery . Over 5 Million Images Processed . eClinical Technology Suite . 21 CFR Part 11 Compliant . Integrated Data Management . Clinical Trial Data Analysis . Electronic Case Report Forms . Forms Library . Clinical Study Documents . Sophisticated Edit Checks . Verication . Protocol Design . Image Identication . Data Management . Image De-identication . CDISC . CDASH . Pivotal Trials . CNS . Expert Readers . Integrated Lab Data . CRO Partnerships . Predictable Pricing . Electronic Trial Expertise . Radiology . Film . Electronic Image Transmission . Drug Supply Chain . Patient Diaries . ePRO . Patient Reported Outcomes . Biomarkers . IVR/IWR . Parameter Driven IWR . EDC Integration . Diagnostic Agents . Faster Database Lock . FDA-compliant . RECIST . Cheson . Global Capabilities . Adaptive Trials . Real-time Data Access . IVR . Parameter Driven IWR . Pluggable Custome Code . Custom Data . Highly Scalable . Clinical Trial Supply Forecasting . Monte Carlo Statistical Simulations . Advanced Reporting . Pooled Drug Supply Across Protocols . Variable Dosing . 360o Integration . Industry-leading . Help Desk . Interactive Voice Response System . Interactive Web Response System . Full Service EDC . Clinical Trial Management System . CTMS . Bio-READ . Bio-TRACK . Bio-PACS . Bio-DXA . Global . Independent Blind Read . State-of-the-art . Global Capabilities . DXA . CT . Safety . Next-generation Interactive Web Response System . Ultrasound . X-ray . BioClinica Express . BioClinica Optimizer . BioClinica WebView . BioClinica WebSend . BioClinica Trident . Efcacy . Global Clinical Trial Solutions . Real-world Results . Imaging Core Lab Services . eClinical Services . Clinical Trial Supply Simulation . Imaging Endpoints . EDC Integration . FDA-Compliant . MRI . Nuclear Medicine . PET . Imaging Endpoints . 2,000 Clinical Trials . International Clinical Trials . 11,000+ Site Managed . 80+Countries . Global . 27/4 Support . Site Training . Data Collection . Data Management . IVR Quality Control . Best-of-breed . Cardiology . Musculoskeletal . Osteoporosis . Osteoarthritis . Rheumatoid Arthritis . Oncology . Neurology . Efcacy . Diagnostic Agents . Clinical Trial Forecasting . Simulation . Buffer Stock Optimization . Clinical Trial Management . Imaging Core Lab . Therapeutic Expertise . Data Collection Expertise . Electronic Data Capture . Certied Radioloogist . Image Quality Control . Angiography . Phase I-IV . Clinical Data Management . FDA-compliant . Medical Image Management . CTMS Solutions . Innovative Technologies . Parameter Driven IWR . Global Delivery . Over 5 Million Images Processed . eClinical Technology Suite . 21 CFR Part 11 Compliant . Integrated Data Management . Clinical Trial Data Analysis . Electronic Case Report Forms . Forms Library . Clinical Study Documents . Sophisticated Edit Checks . Verication . Protocol Design . Image Identication . Data Management . Image De-identication . CDISC . CDASH . Pivotal Trials . CNS . Expert Readers . Integrated Lab Data . CRO Partnerships . Predictable Pricing . Electronic Trial Expertise . Radiology . Film . Electronic Image Transmission . Drug Supply Chain . Full Service EDC . Clinical Trial Management System . CTMS . Bio-READ . Bio-TRACK . Bio-PACS . Bio-DXA . Global . Independent Blind Read . State-of-the-art . Global Capabilities . DXA . CT . Safety . Next-generation Interactive Web Response System . Ultrasound . X-ray . BioClinica Express . BioClinica Optimizer . BioClinica WebView . BioClinica WebSend . BioClinica

Authors: Harris Ahmad, MD* Colin G Miller, Ph.D.* Dong Xu, MS** Dsire van der Heijde, MD, Ph.D.*** *Medical Affairs, BioClinica Inc., **Clinical Data Management, BioClinica, Inc., ***Rheumatology, Leiden University Medical Center BIOCLINICA, Newtown, Pennsylvania, USA email: harris.ahmad@bioclinica.com

EULAR11-1878 BACKGROUND:
In the evaluation of rheumatoid arthritis in double blind, randomized clinical trials, radiographic progression is scored as a measure of efcacy according to validated methods such as the modied Sharp scoring method [1] and modied van der Heijde Sharp method [2] for assessment of erosions and joint space narrowing in select joints of the hands and feet. A pair of readers whom are both blinded to time point has been accepted by the regulatory agencies for submission for approval of biologics in rheumatoid arthritis and other indications. [3, 4] If a signicant difference in change score between the two readers as compared to baseline results, a 3rd reader, or adjudicator evaluates the radiographs. This difference in change score as compared to baseline has historically been selected to be between 7 and 15 points. Furthermore, the regulatory authorities suggest a cause for concern if 20% or more of the cases have resulted in adjudication for a clinical trial. However, no predictive model has been presented in the literature that would determine the number of cases that would result in adjudication at a predened difference in change score.

RA STUDY ADJUDICATION THRESHOLD VS ADJUDICATION RATE

12.0

RESULTS:
The results demonstrate the percentage of adjudicated cases is inversely related to the threshold for difference in readers change score from baseline. It is evident that the higher the number of time points per reading session, the higher the adjudication rate for the same threshold in change score as there are also more comparisons per patient. Furthermore this is accentuated with the lower number of change score that is evaluated.

10.0 Adjudication Rate (%)

CONCLUSIONS:

In conclusion, as expected, the higher the adjudication threshold, the lower the number of image sets that require adjudication. Adjudication rates are of minimal magnitude with any threshold selected even as low as 6 points and most importantly well below the maximum acceptable rate of 20% as considered by the FDA. This data provides scientic rational for the most appropriate threshold for adjudication for design of studying experimental therapeutics in clinical trials for Rheumatoid Arthritis using the modied van der Heijde Sharp method. The adjudication rate using modied van der Heijde Sharp method is than the 20% rate required by the FDA using well calibrated readers regardless of the number of time points or threshold selected.

8.0

OBJECTIVES:
To provide a predictive model for the anticipated number of cases to be adjudicated as a percent based on a predetermined threshold and the number of time points per reading session.

6.0

METHODS:
19 Phase II and III clinical trials for the approval of a biologic for Rheumatoid Arthritis with over 9000 patients and 25,000 time points were analyzed. Radiographic progression was scored by experienced readers using the modied van der Heijde Sharp method (total status score of 448). Trials were scored by 14 readers with 13 reader pairs. No imputation was involved in calculating the total score and total change score from baseline. Only complete joints being scored were included in this study. Patients who had missing joint scores resulting from inadequate image acquisition and joint surgery were removed from this study. In all 19 studies. 2 primary readers independently read radiographs in campaigns which consisted of 2 or more time points in a blinded fashion on a 21 CFR Part 11 compliant imaging read system employed by BioClinica, Inc. The range of study size and total time points grouping by the number of time points are provided in Figure 1. The databases were analyzed to yield the theoretical number of cases that would be adjudicated by a 3rd reader based on a predened threshold for difference of change score between 2 readers as compared to baseline.
Number of Time Points per Reading 2 3 4 Number of Studies 3 13 3 Range of Study Size 426 ~ 591 93 ~ 1008 172 ~ 483 Total Time Points 3124 18951 3700

4.0

REFERENCES:
2.0
[1] Sharp JT, Young DY, Bluhm GB, Brook A, Brower AC, Corbett M, et al. (1985) How many joints in the hands and wrists should be included in a score of radiologic abnormalities used to assess rheumatoid arthritis? Arthritis Rheum; 28:132635. [2] van der Heijde DM. (1989). Effects of hydroxychloroquine and sulfasalazine on progression of joint damage in rheumatoid arthritis. Lancet 1(8646): 1036-1038.

0.0 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Difference between Two Readers Change Score from Baseline (Threshold)

2 time points within one reading session 3 time points within one reading session 4 time points within one reading session

[3] Guidance for Industry: Clinical Development Programs for Drugs, Devices, and Biological Products for the Treatment of Rheumatoid Arthritis (RA) February 1999. [4] Committee for the proprietary medicinal products (CPMP). Points to consider on clinical investigation of medicinal products other than NSAIDS for the treatment of rheumatoid arthritis. December 2007.

Figure 1: Study breakdown by number of patients and number of time points.

Figure 2: The graph displays the percent adjudicated cases in relation to the threshold for difference in change score from baseline between two readers.

Annual European Congress of Rheumatology EULAR 2011 London, United Kingdom May 25 28, 2011