David R. Holmes, Jr., M.D. Mayo Clinic, Rochester Beyond the IDE Study: Post Market Surveillance Progress Report on the TVT Registry David R. Holmes, Jr., M.D. Mayo Clinic, Rochester CRT 2013 Washington, DC February 2013 test

I have no real or apparent conflicts of interest to report. David R. Holmes Jr. MD I have no real or apparent conflicts of interest to report.

Rational Dispersion of New Medical Devices Safety Effectiveness Access to Care

“The FDA should develop a comprehensive medical device postmarket surveillance strategy to collect, analyze and act on medical device postmarket performance information” The FDA 510(k) Clearance at 35 Years IOM July, 2011

JAMA, Nov. 2011; 306

National Coverage Determination TAVR is covered for treatment of symptomatic AS when furnished according to an FDA approved indication System has received FDA PMA for an approved indication 2 cardiac surgeons have independently examined and evaluated suitability Heart team

National Coverage Determination “TAVR is covered for uses that are not expressly listed as an FDA approved indication when performed within a clinical study that fulfills all the following.”

Post Market Surveillance Device performance in the wider community What Happens Next? Post Approval Studies Post Market Surveillance Designed to assure continued safety and efficacy addressing specific questions Device performance in the wider community

Post Approval Studies Vary in design and scope Assessment of device performance and risk benefit ratio through PLC Study specific endpoints of concern – stroke Identify unexpected serious risks – e.g. device failure May focus on population used for approval or expand to other populations Track real world introduction including selection creep, device iteration

Post-market Surveillance: Goals The numerator and denominator of patients receiving a device are both crucial Primary goals are the assessment of effectiveness and safety when applied in clinical practice for ALL patients who receive the device, not a subset Use existing infrastructure of national clinical data repositories to capture ALL patients undergoing device placement: ACC/NCDR and STS

IDE Traditionally corporate sponsor Selected sites Data resides with corporate sponsor Issues of full access/full reporting Adverse events reporting

Alternative Access Background FDA approved in November 2011 Inoperable patients Femoral access Problem Many patients not suitable for TF procedures

Alternative Access IDE and protocol approved Jan. 17, 2013 Research study using TVT Registry as data collection platform Approaches Transapical Transaortic Trans-subclavian/axillary Trans-iliac

Alternative Access Prospective study 1000 patients until Dec. 31, 2018 CMS reimbursement anticipated for eligible patients enrolled in this research study Local consent form approved by local IRB sufficient provided that there is documentation of discussion about AA

“The FDA should develop a comprehensive medical device postmarket surveillance strategy to collect, analyze and act on medical device postmarket performance information”

PAS Industry TVT Registry 1200 patients All TVT patients, all centers 35 sites 5-year follow-up Extra fields required All TVT patients, all centers Negotiate TVT elements with FDA, CMS 5-year follow-up

Cumulative TVT Registry Sites Enrolled (2012-2013)

Establishing the Registry February 2011 Discussions between FDA, ACC and STS July 2011 TVT Registry proposed at the FDA Advisory Panel for Edwards Sapien Valve November 2011 Edwards Sapien THV approved in U.S. Dec 2011 STS/ACC TVT Registry launched May 2012 CMS issued a NCD for transcatheter valves mandating participation in a national registry as a requisite for reimbursement July 2012 TVT Registry v1.1 launched

Current Status 150 sites enrolled 1500 patient records Nested registry for PAS 2 for Edwards Sapien Valve

Regulatory Issues Industry Training, credentialing, ? policing One hurdle after another Long delays, pre IDE studies, PAS, PMS Changing regulatory climate Changing endpoint analyses Lengthy expensive – PAS, PMS, IDE Non-approved indications Support new and old technology Adverse event reporting

Is regulatory process too lax? Conclusion: Premarket approval of cardio- vascular devices by the FDA is often based on studies that lack adequate strength and may be prone to bias

UDI system incorporated into EHR National and international device registries Modernize adverse event reporting New methods for evidence generation, synthesis and appraisal

Post-market Surveillance: What is Involved Infrastructure, well-designed data forms to allow seamless collection of data for: New iterations of the device(s) New adjunctive strategies (embolic protection, etc.) Changes in approach (transapical, subclavian, transfemoral) Changes in patient selection criteria and outcome over time

National Coverage Determination TAVR is covered for treatment of symptomatic AS when furnished according to an FDA approved indication System has received FDA PMA for an approved indication 2 cardiac surgeons have independently examined and evaluated suitability Heart team

Clinical Research Study Outcome measures defined Principal purpose is to test whether a particular intervention improves outcome Does not duplicate existing studies Scientific integrity http://www.icmje.org Registered on clinical trials.gov Protocol approval by CMS Public reporting of data, monitoring prespecified

IDE Facilitate reimbursement by CMS Foster study in broader patient groups, e.g. PTCA Empower unbiased scientific study and reporting Result in expanded approved indications

IDE Elements Written protocol: methodology Investigator certification Local IRB approval Informed consent All data forms Device manufacturing details Prior investigations Written monitoring procedures Detailed Description Monitoring and reporting SAE Annual progress reports

IDE Issues Site selection, IRB involvement Protocol development Informed consent Monitoring Adverse event reporting Funding Who will do the work and hold the IDE

Post-market Surveillance: Goals The numerator and denominator of patients receiving a device are both crucial Primary goals are the assessment of effectiveness and safety when applied in clinical practice for ALL patients who receive the device, not a subset Use existing infrastructure of national clinical data repositories to capture ALL patients undergoing device placement: ACC/NCDR and STS

Registries A Platform for Phase 3 and 4 Studies Pre-Market Post-Market Role for New Generation of Clinical Registries Phase 4 P-Market Phase 1 Phase 2 Phase 3 P-Approval Registries Safety #1 EP Small sample Highly selected Short duration Safety & efficacy Limited sample Highly selected Short duration Safety & efficacy Larger sample Selected Pivotal (RCT) Longer duration FDA driven Centers defined P3 continuance Sample predet Time predet Sponsor driven RCT; claims based Comparisons Costs collected Sample predet Time predet Effectiveness #1 EP Performance & safety Hypothesis generating Large Sample undefined Real world population Continuous duration Rx not assigned

The Partners STS ACC DCRI TVT Registry FDA CMS NHLBI Edwards Lifesciences CMS NHLBI

The Partners STS ACC DCRI TVT Registry FDA CMS NHLBI Corporate

Hospital Variation for Inappropriate PCI We’re here Hosp (no.) 0 10 20 30 40 50 60 Hospital rate of inappropriate PCI procedures (%)

Hospital Variation for Inappropriate PCI We’re here Hosp (no.) 0 10 20 30 40 50 60 Hospital rate of inappropriate PCI procedures (%)

Post Approval Studies History Typically FDA mandated, industry supported Little harmonization of definitions or data specifications Specific patient populations – numerator known but no denominator Do not track device iterations Conflict of interest Typically no blend of clinical and administrative data

Societal Registries What could they offer? Harmonized objective audited data Sophisticated analytics without COI Blend clinical and administrative data Capture all procedures – numerator + denominator Capture medically treated patients Track device iterations and changes in patient selection Serve as FDA, CMS mandated studies

STS/ACC TVT Registry New outcomes registry of TAVR, approved in the U.S. November 2011 >400 data elements Web based data entry Standardized data elements – VARC definitions 30 day risk adjusted clinical outcomes Linked to CMS claims data for long term outcomes Will be harmonized with STS database for surgical AVR

STS-ACC National TCV Registry The Vision Creation of a generic platform Infrastructure for Pre-market IDE device submission Post-market surveillance “Off indication” evaluation (CED) Generic for different devices and device iterations Develop comprehensive infrastructure for disease management Comparative effectiveness analysis Cost effectiveness research Appropriateness of care analysis Quality monitoring Performance improvement opportunity Observational and hypothesis-driven studies of “real world” practice

Role for new generation of clinical registries Pre-market Post-market Role for new generation of clinical registries Phase 4 Phase 1 Phase 2 Phase 3 Post- approval Post- market Registries

TVT Registry Governance Industry NHLBI Payor (non-Medicare) Consumer Reports Patient Representative Public Healthcare System ARHQ Steering Committee Research and Publications Subcommittee Stakeholder Advisory Group

Steering Committee STS Members ACC Members Registry Operations Center Fred Edwards Fred Grover Michael Mack Dave Shahian ACC Members Ralph Brindis John Carroll David Holmes Murat Tuzcu Registry Operations Center NCDR Data Analytics Center DCRI – Eric Peterson Matt Brennan Ex Officio Members FDA – Danica Marinac-Dabic CMS – Jyme Schafer NHLBI – Frank Evans Chair TVT R&P Subcommittee – John Rumsfeld Staff Cynthia Shewan Hilary Kirk Tony Hermann Kathleen Hewitt Barb Chiistensen

Establishing the Registry February 2011 Discussions between FDA, ACC and STS July 2011 TVT Registry proposed at the FDA Advisory Panel for Edwards Sapien Valve November 2011 Edwards Sapien THV approved in U.S. ACC and STS filed a request with CMS for a NCD for transcatheter valves Dec 2011 STS/ACC TVT Registry launched May 2012 CMS issued a NCD for transcatheter valves mandating participation in a national registry as a requisite for reimbursement July 2012 Web-based data entry portal opened

TVT Registry Challenges Start up and ongoing costs Compliance/participation Burden of data collection/entry Completeness of data collection Auditing/data accuracy Linking of TVT registry with CMS data Research questions

Outcome Report Metrics In hospital Mortality & adverse events Procedure success Acute kidney injury 30-day and 1-year outcomes All cause mortality Stroke MI Bleeding events Valve performance Quality of life (KCCQ)

Data Quality Site training and support Data integrity checks Data audits Adjudication of selected events Stroke TIA Aortic valve re-intervention

Innovative Aspects of TVT Registry Capture of all devices (mandated for reimbursement) Will incorporate UDIs Immediate focus on critical issues Short-term risk adjusted clinical outcomes Long-term outcomes by linkage with CMS claims data Quality of life outcome data Risk prediction algorithm will be developed Appropriateness of use assessment Expansion of FDA “label” indications Nested PAS studies

TVT Registry Funding Initial start-up expense borne by the professional societies Ongoing expense funded by site initiation and annual participation fees Funding received from Edwards Lifesciences for PAS study

Development of the TVT Registry “The Good” New collaboration between many partners Capability for robust post market surveillance Expansion of the role of registries

Development of the TVT Registry “The Bad” Burdensome data collection for sites Initial and annual expense for sites Site agreements, contracts, informed consent Communication between all stakeholders is a constant challenge in “uncharted waters”

Development of the TVT Registry “The Yet to be Determined” Different stakeholders have different goals FDA “Safe and effective” CMS “Reasonable and necessary” Professional Societies “Appropriate use”, guidelines

TVT Registry Next Steps Annual reports at society annual meetings Linkage with CMS database for long-term outcomes Develop TAVR risk model Global harmonization of this registry with OUS databases/studies based on VARC common definitions Extension to pre-market use Link with STS Adult Cardiac database for comparative effectiveness with surgical AVR

STS-ACC National TCV Registry Precedents INTERMACS Registry – NIH ACC-NCDR National ICD Registry – Expanded Indication PAS – MADITT II with BSC ASCERT Trial – STS-ACC NHS TAVI CCAD National Database – United Kingdom GARY – German Aortic Valve Registry STS-SSMDF Linkage for cardiac surgery long-term outcomes