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

2. 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.

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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.

9. 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

10. 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

11. Core Laboratories in Clinical Trials: Standardized Process1
Image Acquisition 2
Recording and Sending 3
Tracking Media 4
Data Analysis 5
Data Entry (Database)

12. MRI Core Laboratory Inter-reader Intra-reader -10 10 20 30 40 50 6010 20 30 40 50 60
ROI(g)a-2nd 70
ROI(g)c
Y = * X; R^2 = .99
Regression Plot
-10 10 20 30 40 50 60
ROI(g)a-1st
ROI(g)a-2nd
Y = * X; R^2 = .992
Regression Plot

13. 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