1. Leveraging Registries and Real-World Evidence Through the Total Product Life Cycle (TPLC)
Karen Ulisney, M.S., CRNP
Clinical Trials Program
Office of Device Evaluation
Center for Devices and Radiological Health

2. Disclosures
I have no financial conflicts of interest and am a full time employee of the FDA

3. What is a RWD/RWE?
RWD – Data collected from sources outside of “traditional” clinical trials
RWE – Evidence derived from aggregation & analysis of RWD

4. 3 Key Dimensions of RWE and Registries
The setting where the evidence is generated; real world vs. traditional trials, e.g., population defined by the data source, processes in place to Collect and Curate the data.
The methodological approach used to conduct and Analyze the surveillance or research activity is prospectively defined.
The ability to Act on new information generated by RWE
Source – Califf,R; Real World Evidence – What Is It and What Can It Tell Us? NEJM 12/8/16

5. How Are Registries Used Along the TPLC
Development and Pre-Clinical- Early Clinical
IDE Pivotal Trial
PMA Review - Approved
Post Approval Studies Surveillance (UDI tracking)
Device Iterations, OPC, Practice Guidelines, Payer, Safety Signals, Labeling Updates
Post-Market
Pre-Market
ACC/ NCDR Registries – TVT, CATH PCI, LAAO
VQI Registry
Follow device through TPLC -Pre/Post Market Balance
Avoid duplicate data collection
Increase operational efficiencies
Decrease costs/time developing/conducting trials
PAS- timely completion & longitudinal surveillance (CRN - linked databases)

6. Examples – RWE Use / CV Registries
Post Approval - CoA
Surveillance Activity – Linked to Payer requirement (CED / longitudinal follow-up)
Pre-Market Expand Indications for Use
(observed use in real world setting – commercially available devices)
Pre-Market Control Cohort and Post Approval CoA Surveillance Activity
TAVR – Approved Intermediate- Risk patients post approval CoA surveillance activity also met CMS CED requirements
STS/ACC TVT Registry
TAVR – Alternate Access for device delivery
Peripheral Vascular Angioplasty – Comparator arm, propensity-scored, prospectively designed. Post-Approval Surveillance
VQI Registry
LAAO – Stroke prevention – A-fib patients. FDA worked with CMS to align NCD/CED with the ACC/NCDR LAAO Registry post approval CoA Surveillance activity
DES – Expand to diabetic population.
ACC/NCDR CathPCI Registry
Surgical Aortic Valve Replacement –
Comparator for an effectiveness endpoint for surgical times. Labeling claim to shorten operative time.
STS Adult Cardiac Surgery Registry

7. Examples – RWE Use / CV Registries
Other: MDEpiNet
Study Design – Clinical Investigation
SAFE-STEMI for Seniors
DCRI, ACC/NCDR CathPCI Registry, CMS Claims Data.
Software interface developed to auto populate registry data to the study CRF. Study supports 2 independent IDEs
Prospective Registry base study of STEMI patients >64 undergoing primary PCI via the radial access randomized to either infarct-artery PCI only vs. complete revascularization. Aims – to Assess
Major bleeding comparing radial vs. femoral artery access
1-year outcome of infarct-target vessel failure and MACE comparing a drug-eluting vs. bare metal stent and comparing infarct-artery PCI only vs. complete revascularization
RAPID – Registry Assessment of Peripheral Interventional Devices
(Project emerged from PASSION - Predictable and SuStainable Implementation of National Registries for CV Devices)
Development of a structured core clinical data set, including UDI, implemented across existing registries and EHR systems.
Interoperable data from multiple sources for clinical research and device evaluation initiatives.

8. RWE Decisions Today
The RWE implementation team is working with Industry and our ODE Review Teams to leverage RWE use for regulatory decisions along the TPLC. Key areas of assistance provided by our team includes;
Data handling and consent questions
Data Quality Metric - Fit for Purpose
Relevance - adequacy and analysis of the data source. Does the data source adequately address the regulatory question or requirement?
Reliability – applies to the quality of the data source. How was the data accrued and is it accurate? Is there a Registry data management SOP manual? How is the data monitored/audited ? Is data assurance provided; missing data minimized?

9. RWE Decisions Today
Study design and analytic methods and tools for data linkage or CRN (MDEpiNet and other case examples )
When is an IDE needed for Registry Studies?
Post Approval requirements – Surveillance activity, PAS
Label expansion; additional considerations - Appropriate endpoints or outcomes of interest, data source(s)/capture, how to minimize bias, the appropriate comparators, the type of data auditing/ monitoring needed, benefit/risk calibrated to the level device development, incorporate patient perspective concepts when possible

10. RWE Gap Areas Under Development
Patient data access limitations e.g., de-identification methods
Embedding IDE trials in Registries – moving in this direction and growth expected this year.
Incorporate patient preferences concepts into registry studies
Seamless linkage and timely reporting of RWD from other sources (e.g., EHR, Claims and other Registries)
EHRs largely unstructured and lack interoperability with other data platforms and UDI implementation needed
Expand study design options (e.g.; and analytic methods and tools for data analysis
Practical strategy for conducting data quality assurance

11. RWE Future - How Can We Improve?
Medical Device User Fee Amendments (MDUFA IV) Commitment – F/Y 2018
RWE - FDA commitment to robust policy development and facilitate the application of RWE in Regulatory decision making
FDA fund NEST Coordinating Center (MDIC) – pilot projects and infrastructure to support use of RWE.
Facilitate the use of RWE along the TPLC – e.g., leverage architecture from existing registries and explore industry models, stand up Registries in other product areas as appropriate for TPLC, integrate into the clinical workflow, improve ability to extract, scale, link, use EHR and claims data, UDI implementation necessary, apply quality metrics, engage all stakeholders in identifying needs/solutions, & address key concerns and publish final guidance on RWE Use for Regulatory Decisions.
FDA will not require post-market surveillance studies for devices where registries and/or RWD sources exist if FDA has access to the RWD source and has determined the RWD source is sufficient to take the place of a post-market surveillance study.

12. RWE Future - How Can We Improve?
Consent Issues and Patient Involvement
Legislative – 21st Century Cures Act (Central IRB, Waiver of informed consent for minimal risk studies, broad consent in clinical and research consents for future data use – harmonize with the Common Rule)
Improve patient engagement at all levels of Registry operation (capture EPs important to patients e.g., QoL, disability, cognitive function and pain)
Other
Strengthen collaborations and understand the needs of Stakeholders - Industry, Regulators, Payers, Professional Societies, Providers, Patients
Templates for Contracts and Agreements nuanced for use of Registries and RWD/RWE

13. Bottom Line
Registries can provide a useful tool in providing evidence for regulatory decisions along the TPLC
Work with FDA to address unique aspects of registry use and opportunities to use RWE for regulatory decisions
Additional test cases are needed to optimize the potential benefits of registry use and to develop standard practices

14. Questions?