Clinical Trial Organization Core Laboratories A Crucial Component of Clinical Research Alexandra Lansky, MD Professor of Medicine, Section of Cardiology Yale School of Medicine

Disclosure Statement of Financial Interest I, Alexandra Lansky, DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

Core Laboratories in Clinical Trials: Standardize Data Collection and Endpoints Independent Core Laboratory ensures standardized, reproducible and unbiased evaluation of endpoints Definitions: Standard well accepted/consensus Measurements: Systematic and validated Methodology: Accepted and validated for reproducible endpoints Understanding the patho-biology of endpoints Impact of timing of event assessment Impact of intervening test measures on clinical endpoints

Guidance for Industry and FDA: Heart Valve IDE and PMA applications ECHO Core Laboratory Guidance for Industry and FDA: Heart Valve IDE and PMA applications ISO 5840:2005 annex H provides information regarding the echocardiography protocol (recording studies, data collection, and core laboratory calculations and analysis). In addition FDA recommends: An echocardiography core laboratory for the central review of all echocardiographic data. A supervising director experienced in valve echocardiography. Use of a written echocardiography protocol Blinded interpretation of the echocardiograms The core laboratory interpretation of echocardiograms takes precedence over site reads

Core Laboratories in Clinical Trials: Provide Reliable Endpoint Measures Primary or secondary endpoint measures: Efficacy surrogates (LLL, RS) Safety measures (Aortic regurgitation after TAVI) Adjudication of Clinical Events Revascularization Stent thrombosis Myocardial Infarction Mechanistic insights of performance IVUS/OCT ECHO

Angiographic Core Laboratory PCI/Stent Trials Independent Adjudication of all Revascularizations TLR vs TVR vs Non TVR Thrombosis Surrogate measures of device efficacy Validated surrogate Restenosis LLL Stent versus Lesion/segment Identify qualifying angiogram for endpoint measure In case of multiple follow-up angiograms, identify which angiogram is used for endpoint measurement

Core Laboratories in Clinical Trials: Standardize Data Collection and Endpoints CRF Design Design of CRF (endpoint measures) tailored to protocol and knowledge of software capabilities for valid reproducible analysis CRF programming requires validation and build in cross checks Data entry requires 100% QC if single entry, less if double entry Site training > 50% of endpoint measurement variability can come from differences in site acquisition Provide detailed, but easy to use instructions to the sites to acquire samples/media in a standard manner to ensure data consistency and quality

Core Laboratories in Clinical Trials: Site Training and Feedback Acquisition Guidelines for Sites We require the following information from the sites to ensure quality and accurate data from the echocardiographic images: A simultaneous ECG with a clearly defined R-wave. At least 2 two beat loops for all image acquisition. Doppler waveforms recorded at sweep speeds of 50 or 100 mm/sec. If 2 contiguous segments of the myocardium is not well visualized contrast injection should be used and labeled in each contrast image.

Core Laboratories in Clinical Trials: Standardize Data Collection and Endpoints Core Lab analysis Trained personnel with current training records, daily feedback, weekly training sessions, and annual training updates Establish a standard process for the Core lab cycle: receiving, labeling, analyzing, reviewing, managing data, and communicating with data management group and sponsor QC of analysis varies: US standard is 100% review of technical aspects of analysis Inter and Intra reader validation with measurement accuracy and precision of quantitative and qualitative measures Process, validations, analysis must be detailed in SOPs and maintained current

Core Laboratories in Clinical Trials: Standardize Data Analysis, Definitions Qualitative analysis: Lesion morphology Lesion length Blood flow Distal run-Off Complications: Thrombus Dissections Abrupt closure Perforation No reflow Spasm Distal embolisation Quantitative analysis Proximal RVD Distal RVD Interpolated RVD Minimum lumen diameter

Core Laboratories in Clinical Trials: Standardized Process 1 Image Acquisition 2 Recording and Sending 3 Tracking Media 4 Data Analysis 5 Data Entry (Database)

MRI Core Laboratory Inter-reader Intra-reader -10 10 20 30 40 50 60 10 20 30 40 50 60 ROI(g)a-2nd 70 ROI(g)c Y = -.006 + .978 * X; R^2 = .99 Regression Plot -10 10 20 30 40 50 60 ROI(g)a-1st ROI(g)a-2nd Y = .318 + .955 * X; R^2 = .992 Regression Plot

Conclusions Central Laboratories Important component of most clinical trials Provides independent unbiased analysis Laboratory qualifications and validation ensures consistent reproducible results Assists in the accurate and independent adjudication of clinical events