QA & imaging biomarkers within the framework of clinical trials L Fournier, Y Liu, N de Souza, P Bourguet For the Imaging Group - EORTC Imaging biomarkers in clinical trials: role Clinical trial = validation of the imaging biomarker Imaging biomarker Imaging biomarker = endpoint of clinical trial 2 Imaging biomarkers in clinical trials: role Clinical trial = validation of the imaging biomarker Imaging biomarker Imaging biomarker = endpoint of clinical trial 3 Imaging biomarkers in clinical trials • In oncology clinical trials: imaging is almost always present • “Endpoints for FDA approval in oncology drugs” Johnson, JCO 2003;21:1404-1411 • 1990-2002: 57 molecules approved • 18 (32%) on OS • 29 (51%) on response criteria or PFS MEASURED ON IMAGING 4 Imaging biomarkers: interrogating biology Diffusion MRI PET- FDG Cellularity Cell metabolism MRSpectroscopy Molecular composition Perfusion imaging Angiogenesis BOLD MRI Hypoxia O O2 2 O2 Hanahan & Weinberg, Cell 2011 Innovative imaging biomarkers: hurdles • Upstream • Technical validation understand the conditions for reliable quantification • Clinical trial • Complexity of imaging technologies • Safety issues related to new imaging contrast agents • Standardisation of image acquisition across multivendor platforms • Variable post-processing options Centers selected for their clinical not their imaging expertise 6 Upstream: technical validation • Pre-clinical and clinical phase • Phantom studies • Repeatability (test-retest) • Reproducibility • Variability between machines • Variability between image processing techniques Upstream: technical validation ADC: apparent diffusion coefficient Repeatability studies 15-20% CV Variability of ADC in abdomen Donati, Radiology 2009 Kim, Radiology 2010 Upstream: technical validation QuIC-ConCePT (Quantitative Imaging in Cancer: Connecting Cellular Processes with Therapy) : an IMI funded project • 18FLT-PET and ADC (1.5T and 3T) • Technical (and biological) validation • N De Souza, Institute of Cancer Research and Royal Marsden Hospital • Y Liu, EORTC Upstream: technical validation Phantom studies BW= 1776 Hz/px Courtesy of N De Souza BW=2442 Hz/px ADC profile Fat suppression Ghosting Uniformity Upstream: technical validation Test-retest & repeatability studies: after standardisation/optimisation Courtesy of N De Souza Variability of ADC in ovarian cancer <5% Variability of ADC in lung (1.5T) <10% Routine biomarkers: size Thiam, Fournier ECR 2010 Reproducibility study: RECIST size criteria RECIST 1.0 RECIST 1.1 Kappa Intra Inter Intra Inter Target 0.82 0.90 0.82 0.78 lesions Non target 0.90 0.95 0.90 0.95 lesions New 0.58 0.64 0.58 0.64 lesions Total 10-15 % Overall 0.73 0.76 0.80 0.73 response disagreement rate Routine biomarkers: renal function Prigent Semin Nucl Med 2008 Clinical decisions What of Imaging QA Routine imaging biomarkers Current QA Only relevant information 15 Current QA Not relevant with current scanners and reading stations 16 Current QA 17 What of Imaging QA Advanced imaging biomarkers EORTC 62072/VEG110727 phase III clinical trial soft tissue sarcoma What must be avoided pazopanib vs placebo Hypothesis: patients with FDG-PET response (ΔSUVmax ≥ 25%), the PFS is 12 weeks longer than in patients without PET response Day -14 to -1 TKI Courtesy of Y Liu • 44 patients enrolled • 36 BL/33FU PET with good visual quality • Low compliance to the imaging guidelines required %compliance Actual Uptake Time BL 60 ±5 min 39% (15/35) 56-64 min FU 60 ±5 min 51% (18/35) 56-64 min BL+FU 60 ±5 min 31% (11/35) 56-64 min <1/2 patients could be used for FU±5 min from 37% (13/35) 56-89 min quantitative assessment actual BL FU±10 min from 60% (21/35) 56-89 min No conclusion could be drawn due to actual BL inadequate sample size. 19 EORTC infrastructure Courtesy of Y Liu Quality management system • ISO 9001:2000 (AFAQ) • ISO 13485:2003 (GMED) • Annex II section 3 directive 93/42/EEC (Europe) • CMDCAS SQ (Canada) • 510 (k) and the 21 CFR part 11 (US) 20 Easy image EORTC infrastructure uploading direct information export from DICOM header Courtesy of Y Liu Local site case report from Online quality control Easy to measure central review form Automatic email contact to the sites and the manager team 21 Risk management for imaging biomarker-driven studies Trial related documents CLINICAL CENTERS P A Imaging agent production T Scan calibration I 2b. Obtain the accreditations before site activation 3. Enrollment E N INVESTIGOR Recruit and treat patients T 2a. Obtain the approvals of regulatory bodies Quality Assurance & Quality Control CLINICAL DATA 1. Trial development IMAGING PLATFORM Liu et al, Lancet Oncol 2015 Central review 6. Imaging Imaging 6. analysis Reader 1 Reader 2 Adjudicator Trial monitoring and management • Early engagement with experts • Preliminary data Protocol design • Understanding of biological mechanism • Selection of appropriate criteria • Early definition of statistical consideration Courtesy of Y Liu • Involving patient advocacy • Site selection Before site • Evidence of scanner calibration activation • Elaboration of standard operating procedures • Organization of imaging central review • Evidence of proper site training • Data protection • Compliance electronic processes During accrual • Perform quality assurance and quality control • Data management and tracking • Documentation At the end of • Closure of database the trial • Statistical analysis and report Conclusion • We should be able to do better than size! • Metabolic imaging, Diffusion-weighted MRI • Involve imaging specialists when designing the trial • Choose the right technique, criteria & know its limits • Reasonable & manageable protocols (taking into account different levels of expertise) • Allocate resources ($$ and personnel) • Even advanced imaging is cheaper than most targeted therapies 24 .