1. 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

2. 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.

3. Rational Dispersion of New Medical Devices
Safety Effectiveness
Access to Care

4. “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

6. JAMA, Nov. 2011; 306

8. 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

9. 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.”

10. 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

11. 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

12. 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

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

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

16. 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

17. 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

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

19. 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

20. Cumulative TVT Registry Sites Enrolled (2012-2013)

21. 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

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

23. 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

24. 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

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

26. 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

27. 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

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

29. 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

30. 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

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

32. 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

33. 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

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

36. The Partners STS ACC DCRI TVT Registry FDA CMS NHLBI Corporate

38. Hospital Variation for Inappropriate PCI
We’re here
Hosp (no.)
Hospital rate of inappropriate PCI procedures (%)

39. Hospital Variation for Inappropriate PCI
We’re here
Hosp (no.)
Hospital rate of inappropriate PCI procedures (%)

40. 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

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

49. 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)

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

51. 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

52. 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

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

54. 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”

55. 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

56. 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

58. 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