Current Industry Neuroimaging Experience in Clinical Trials Jerome Barakos, M.D.

Transcription

1 Current Industry Neuroimaging Experience in Clinical Trials Jerome Barakos, M.D. Melbourne Australia March 28, 2012

2 Synarc Experience and Expertise Largest imaging service provider dedicated to clinical trials More than 120 ongoing imaging trials Managed 48 AD trials More than 100 MD / PhD employees on staff 25 approvals at FDA/EMA 2

3 Synarc Alzheimer s Disease Experience Phase I 9 clinical trials (# of patients range 30 80), two including amyloid PET Indications: Alzheimer s Disease Geographical distribution: North and South America, Japan, Europe Phase II 11 clinical trials (# of patients range ) Indications: Alzheimer s Disease Geographical distribution: North America / Europe / South Africa / Australia / Asia Phase III 26 clinical trials (# of patients range ) Including 8 PET sub-studies with FDG and/or Amyloid endpoints Indications: Alzheimer s Disease, Vascular Dementia, CADASIL Geographical distribution: North and South America / Europe / South Africa / Australia / Asia / Middle East Phase IV 2 clinical trials (# of patients range 6 300) Indications: Alzheimer s Disease, Mild Cognitive Impairment Geographical distribution: North America 3

4 Sources of variability Subject Scanner Field strength Manufacturer Gradient profile Software version Imaging protocol MRI technologist Software/analysis technique Reader 4

5 Standardization of Imaging Data MRI Protocol Development MRI Site Qualification MRI Site Training Ongoing Image QC Quantitative Image Analysis Software Reader Qualitative Image Analysis Reader 5

6 MRI Protocol Development 1.5 vs. 3.0 T Localizer, Sagittal Spin Echo 3D-T1 MP-RAGE (Siemens)/IR-prep fspgr (GE)/TFE (Philips) Acquire twice Axial 2D Dual echo TSE (Siemens and Philips)/ FSE (GE) Axial FLAIR Axial T2* Gradient Echo Axial DWI 6

7 Standardization of Imaging Data MRI Protocol Development MRI Site Qualification MRI Site Training Ongoing Image QC Quantitative Image Analysis Software Reader Qualitative Image Analysis Reader 7

8 Challenges with MRI Facilities Qualified and trained over 1,200 MRI and CT sites world-wide Inadequate MRI scanner at site Imaging Protocol Compliance: Sites do not follow prescribed imaging protocol Wide variability in types of imaging sites Academic vs private, language barriers, etc. Equipment Upgrades: Software upgrades Hardware upgrades (scanner, gradient, coils) 8

9 MRI Scanner Upgrades 9

10 1.5 vs. 3.0 Tesla Advantages of including 3T Scanners: Account for 17-20% of sites in recent global AD studies More common in sites outside the US Challenges of including 3T Scanners : Requires volumetric analysis sub-study Must be adequately powered to include a sub-study 10

11 Quantitative Image Analysis Quantitative Measures Whole Brain Atrophy/Volume Ventricle Enlargement/Volume Hippocampus Volume Entorhinal Cortex Volume Cortical Thickness etc Standardization of technicians Initial training Initial validation dataset Ongoing Monthly validation Inter and intra-reader variability Retraining for reader drift 11

12 Freesurfer current limitations Reprocess previous timepoints with every new visit Change analysis Slow processing times Whole brain segmentation: 6-8 hrs Cortical parcellations and thickness measurements: hrs Software development not according to 21 CFR part 11 Academic code Running of software not according to 21 CFR part 11 No electronic signatures No audit trails 12

13 NeuroQuant Limitations Designed for clinical practice diagnostic purpose Strict parameter adherence required (single site use) Not all structures are validated Limited reporting capability No custom data transfer options No MCC metrics No DICOM ROI output, color jpeg only No de-identification No timepoint blinding Software not 21 CFR part 11 compliant No electronic signatures No audit trails Only single timepoint 13

14 Applications to Clinical Practice Quantitative Methods Quantitative methods: limited utility in clinical practice Diagnosis and management of patients not dependent on quantitative methods ADNI has provided standard imaging protocols and methods Structural MRI techniques ADNI I Advanced imaging techniques ADNI II fmri on Philips DTI on GE ASL perfusion on Siemens Giovanni Frisoni and colleagues standardizing the hippocampus ROI Hippocampal Harmonization Protocol 14

15 Qualitative Image Analysis Eligibility Assessment To incorporate microhemorrhage/blood product exclusion criteria (i.e. > 4 microhemorrhages, single area of superficial siderosis, evidence of prior macrohemorrhage, etc.) Safety Monitoring ARIA-E: Vasogenic edema/ sulcal effusion ARIA-H: Microhemorrhage < 10mm, larger hemosiderin deposits >10mm, hemorrhage within brain parenchyma, superficial siderosis Presence/absence, location, severity and change from previous 15

16 Qualitative Image Analysis Safety Readings 65,000 MR scans (ARIA qualitative readings) Challenges: Identifying ARIA Requires understanding and familiarity of the imaging abnormalities Requires use of specific MR imaging sequences which allow detection of these abnormalities Standardization efforts Central reading Standardization of readers Initial training Initial validation dataset Ongoing Monthly validation Inter and intra-reader variability Retraining for reader drift 16

17 Sperling et al. Lancet 2012

18 Sperling et al. Lancet 2012

19 Technical Artifact Mimicking ARIA-E

20 Inconsistent quality of FLAIR sequence Incomplete / poor FLAIR water suppression FLAIR

21 Inconsistent quality of GRE T2* sequence

22 Challenge Site Dispute Central Reading Synarc neuroradiologist prepares slides delineating findings Synarc neuroradiologist discusses findings by phone with Site neuroradiologist Documentation: Central Reading Clarification Form 22

23 Applications to Clinical Practice Qualitative Methods Qualitative methods: Findings may be subtle Not common in clinical practice Education is essential First AD drugs may be approved Q Need to identify appropriate patients for therapy Need to monitor adverse events ADNI II is providing standard imaging protocols and methods FLAIR GRE T2* FDA guidance on monitoring of patients in anti-amyloid trials may later be applicable to clinical practice Publications such as Roundtable article of value in this regard 23