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Chief Scientific, Clinical and Regulatory Officer
Randomized Controlled Trials versus Single-Arm Studies (Registries) in TAVI Richard Kuntz, MD, MSc Chief Scientific, Clinical and Regulatory Officer Medtronic
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Medtronic CoreValve® Experience
Over 5000 implants ~200 centers in 27 countries
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CoreValve 18 Fr FIM Safety & Efficacy
Paired 30-Day NYHA Classification Primary Safety Endpoints Outcome Discharged 30-Days* MACE 33 (26.2%) 35 (28.0%) MAE 62 (49.2%) 64 (51.2%) All Cause Deaths 19 (15.1%) 19 (15.2%) Cardiac Deaths 13 (10.3%) 13 (10.4%) Stroke 8 (6.3%) 8 (6.4%) TIA 7 (5.6%) Myocardial Infarction 5 (4.0%) Major Arrhythmia 23 (18.3%) 24 (19.2%) Permanent Pacemaker 37 (29.4%) Major Bleeding 14 (11.2%) Cardiac Perforation 3 (2.4%) Surgical Aortic Valve Conversion Oveall low procedural complications, positive outcomes for patients: Procedure has migrated to truly percutaneous approach, with many of cases done under local anesthesia Adjudicated 18-Fr. S&E trial demonstrates both safety and efficacy with a concomitant improvement in NYHA-FC in high risk patients Published and ongoing studies confirm transferable learning curve Patient survival beyond the early post operative period (30 days) is relatively stable Expanded indication beyond high risk patients must be based on durability of the valve and assessment of QOL The initial early experience with CoreValve 18 French TAVI is encouraging out to two years.
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Long-Term Survival (18-French FIM Safety & Performance Study)
Number at Risk Number Failed Survival (%) 4
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Medical Device Outcomes of Interest
Device performance Does the device itself work as intended? Device treatment effect Does the device change the natural history of the disease or improve the SoC? Device performance and treatment effect in the real world Rare events: device and patient
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Single-Arm Studies: Registries Strengths
Overcome limitations of RCTs in size and duration of follow-up Real world outcomes, broader inference, “wild type” May have an advantage in longer follow-up May detect unknown rare adverse events Qualitative feature, discovery of new hazards
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Single Arm Studies: Registries Weaknesses
Choice of treatment is likely linked to patient characteristics, practitioners, hospitals and procedures. The major inferential question centers on relating the outcome of a patient with the choice of the treatment in question Relating clinical outcomes to treatment choice may thus be confounded by several factors.
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Rationale for RCT in Device Trials
Observational studies may be confounded Device trials are especially vulnerable due to operative covariates and placebo effect The basis of Clinical Evidence Based Medicine is RCT. Medical Devices that are generally developed by for-profit industry sponsors, and objectivity is a requisite
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Clinical Trial Confounders and Other Gremlins That Affect Outcomes And Require Controls
Trial Effects Patient Factors Mechanism of Action Outcome Consistency Ascertain-ment Masking: Placebo Effect Hawthorn Effect Best Operators Best Hospitals Consistent Selection Criteria Consensus on Co-morbid Adjustment Co-Morbidities Willingness to Enroll and Motivation First Wave Reference? Known or Unknown Are there Reliable Surrogates Is the underlying disease altered Hard or Soft Outcome Universal Adjudication Criteria Easily Measured Complete-ness and Consistency of Follow-up
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Single-Arm Studies: Registries Control Measures
Qualitative outcomes Detect rare events, limited comparisons using hard (e.g., mortality) endpoints Require High ascertainment Measures to limit confounding: Propensity score matching, Latent/Instrumental Variables Broad inclusiveness (e.g., Massachusetts PCI database) Specificity Case report forms may be more specific than health care data systems Adjudication of events improves rate estimation precision
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Medical Device Lifecycle Traditional Evaluation Methods
Required Post-market studies, Marketing studies, Physician-sponsored studies, MDRs, Maude Bench Stress & Lifetime Testing Prospective Single Arm & RCTs Ideas, Design, Bench & Mfg Validation Pre-Market Pilot & Pivotal Evaluation FDA/Panel Analysis and Approval Post-Market Studies & Surveillance Next Gen Improvements & Obsolescence
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Medical Device Lifecycle Outcomes of Interest
Device Performance: Durability and Product Safety Device Safety & Durability, Manufacturing Reliability Safety and Efficacy for pre-defined discrete indication Patient Outcomes: Rare Events, Efficacy for Broader Patient & Operator Population Ideas, Design, Bench & Mfg Validation Pre-Market Pilot & Pivotal Evaluation FDA/Panel Analysis and Approval Post-Market Studies & Surveillance Next Gen Improvements & Obsolescence
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Medical Device Lifecycle (Class III) Pathophysiology-Treatment Variables
Broad Patient, Operator Factors Unknown Disease, Device Factors Narrow Patient Factors Clinical, Device Stress Spec d Device Design Bench Measurement Pilot Pivotal Outcomes Device performance Real World Outcomes Rare AE Long-term Effects Ideas, Design, Bench & Mfg Validation Pre-Market Pilot & Pivotal Evaluation FDA/Panel Analysis and Approval Post-Market Studies & Surveillance Next Gen Improvements & Obsolescence
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Medical Device Lifecycle (Class III) Pathophysiology-Treatment Controls
Good method, limited inference by tight eligibility RCT Broad Patient, Operator Factors Unknown Disease, Device Factors Narrow Patient Factors Clinical, Device Stress Spec d Device Design Bench Measurement Pilot Pivotal Outcomes Device performance Real World Outcomes Rare AE Long-term Effects Ideas, Design, Bench & Mfg Validation Pre-Market Pilot & Pivotal Evaluation FDA/Panel Analysis and Approval Post-Market Studies & Surveillance Next Gen Improvements & Obsolescence
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Medical Device Lifecycle (Class III) Pathophysiology-Treatment Controls
Expensive and underpowered method RCT Broad Patient, Operator Factors Unknown Disease, Device Factors Narrow Patient Factors Clinical, Device Stress Spec d Device Design Bench Measurement Pilot Pivotal Outcomes Device performance Real World Outcomes Rare AE Long-term Effects Ideas, Design, Bench & Mfg Validation Pre-Market Pilot & Pivotal Evaluation FDA/Panel Analysis and Approval Post-Market Studies & Surveillance Next Gen Improvements & Obsolescence
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Medical Device Lifecycle (Class III) Pathophysiology-Treatment Controls
Good method, massive sample size to address subsets RCT Broad Patient, Operator Factors Unknown Disease, Device Factors Narrow Patient Factors Clinical, Device Stress Spec d Device Design Bench Measurement Pilot Pivotal Outcomes Device performance Real World Outcomes Rare AE Long-term Effects Ideas, Design, Bench & Mfg Validation Pre-Market Pilot & Pivotal Evaluation FDA/Panel Analysis and Approval Post-Market Studies & Surveillance Next Gen Improvements & Obsolescence
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Medical Device Lifecycle (Class III) Pathophysiology-Treatment Controls
Generally underpowered, follow-up issues RCT Broad Patient, Operator Factors Unknown Disease, Device Factors Narrow Patient Factors Clinical, Device Stress Spec d Device Design Bench Measurement Pilot Pivotal Outcomes Device performance Real World Outcomes Rare AE Long-term Effects Ideas, Design, Bench & Mfg Validation Pre-Market Pilot & Pivotal Evaluation FDA/Panel Analysis and Approval Post-Market Studies & Surveillance Next Gen Improvements & Obsolescence
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Superiority Trial using Binary Restenosis Endpoint (90% Power, 2-sided, alpha=0.05; Assuming Loss to Follow-up = 20%)
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Non-inferiority Trial using Clinical Endpoint (1-sided test, =0
Non-inferiority Trial using Clinical Endpoint (1-sided test, =0.025; 90% Power) 7000 6000 Equiv. Limit 5000 3% 4000 Total N (1:1) 4% 3000 5% 2000 1000 6% 7% 8% 9% 10% 11% 12% 13% 14% 15% Assumed Event Rate Total N is adjusted for 10% loss to follow-up
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Medical Device Lifecycle (Class III) Pathophysiology-Treatment Controls
Poor control, confounded Registry Broad Patient, Operator Factors Unknown Disease, Device Factors Narrow Patient Factors Clinical, Device Stress Spec d Device Design Bench Measurement Pilot Pivotal Outcomes Device performance Real World Outcomes Rare AE Long-term Effects Ideas, Design, Bench & Mfg Validation Pre-Market Pilot & Pivotal Evaluation FDA/Panel Analysis and Approval Post-Market Studies & Surveillance Next Gen Improvements & Obsolescence
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Medical Device Lifecycle (Class III) Pathophysiology-Treatment Controls
Practical, needs high ascertainment (HA) Registry Broad Patient, Operator Factors Unknown Disease, Device Factors Narrow Patient Factors Clinical, Device Stress Spec d Device Design Bench Measurement Pilot Pivotal Outcomes Device performance Real World Outcomes Rare AE Long-term Effects Ideas, Design, Bench & Mfg Validation Pre-Market Pilot & Pivotal Evaluation FDA/Panel Analysis and Approval Post-Market Studies & Surveillance Next Gen Improvements & Obsolescence
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Medical Device Lifecycle (Class III) Pathophysiology-Treatment Controls
Good method, describes practice, HA, representative sample, propensity control Registry Broad Patient, Operator Factors Unknown Disease, Device Factors Narrow Patient Factors Clinical, Device Stress Spec d Device Design Bench Measurement Pilot Pivotal Outcomes Device performance Real World Outcomes Rare AE Long-term Effects Ideas, Design, Bench & Mfg Validation Pre-Market Pilot & Pivotal Evaluation FDA/Panel Analysis and Approval Post-Market Studies & Surveillance Next Gen Improvements & Obsolescence
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Medical Device Lifecycle (Class III) Pathophysiology-Treatment Controls
? Minimally confounded, HA, powered for discovery Registry Broad Patient, Operator Factors Unknown Disease, Device Factors Narrow Patient Factors Clinical, Device Stress Spec d Device Design Bench Measurement Pilot Pivotal Outcomes Device performance Real World Outcomes Rare AE Long-term Effects Ideas, Design, Bench & Mfg Validation Pre-Market Pilot & Pivotal Evaluation FDA/Panel Analysis and Approval Post-Market Studies & Surveillance Next Gen Improvements & Obsolescence
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Have Registries Got it Wrong?
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Biosense Angiogenesis Registry CCS Class Score
P = <.001
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Biosense Angiogenesis Registry ETT: Time to Termination
P = <.001
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Direct (PMR) Exercise Duration
n = 240 patients p = NS p = NS p = NS
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Direct (PMR) CCS Angina Class
(n=298 patients) p = NS p – Values: Groups: p=0.654 Time: p<0.001 p = NS p = NS
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Risk and Restenosis Some Contemporary Clinical Restenosis Rates
Mauri L, Kuntz R
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Risk and Restenosis Some Contemporary Clinical Restenosis Rates
BMS DES Mauri L, Kuntz R
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Have Registries Got it Right?
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Multivariable Predictors of In-Stent Late Loss (N=2426)
Characteristic Effect Estimate (mm) Standard error p-value Stent type (sirolimus-eluting vs. bare metal) -0.833 0.035 <0.0001 Diabetes Mellitus 0.179 0.041 Lesion Length (>14 mm) 0.096 0.0065 Acute Gain (>1.7 mm) 0.133 0.0002 *Reference Vessel Diameter was not an independent predictor (p=0.12) Mauri L, Kuntz R et al. Circulation 2005
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Development of New Evaluation Tools
Stent Evaluation Models O'Malley AJ, Normand SL, Kuntz RE. Application of models for multivariate mixed outcomes to medical device trials: coronary artery stenting. Stat Med Jan 30;22(2): O'Malley AJ, Normand SL, Kuntz RE. Sample size calculation for a historically controlled clinical trial with adjustment for covariates. J Biopharm Stat May;12(2):
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Mass DPH PCI Database 7217 patients: AMI, 4/03 – 9/04 DES-4016, BMS-3201 Propensity sore matching 2-year mortality, repeat revasc, recurrent MI
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Clinical Trial Confounders and Other Gremlins That Affect Outcomes And Require Controls TAVI
Trial Effects Patient Factors Mechanism of Action Outcome Consistency Ascertain-ment Masking: Placebo Effect Hawthorn Effect Best Operators Best Hospitals Consistent Selection Criteria Co-Morbidities Consensus on Comorbid Adjustment Willingness to Enroll and Motivation First Wave Reference? Known or Unknown Are there Reliable Surrogates Is the underlying disease altered Hard or Soft Outcome Universal Adjudication Criteria Easily Measured Complete-ness and Consistency of Follow-up
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RCTs vs Registries for TAVI Conclusions
For TAVI, several confounding factors remain that prohibit the use of a straight registry for the final evaluation of the new therapy against medical or AVR in most patient subsets Preliminary registries have been extremely helpful in demonstrating feasibility and safety outcomes With growing experience and improved co-morbid measurement and risk adjustment, the use of advanced statistical methods for confounding control, consensus non patient selection, and stabilization of the procedure and devices, single arm registries may provide pivotal results for new device generations
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