Regulatory Science: FDA Paths Forward With Real World Evidence Mitchell W. Krucoff, MD, FACC

Regulatory Science: FDA Paths Forward With Real World Evidence 2017 Mitchell W. Krucoff, MD, FACC Professor, Medicine/Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit Director, MDEpiNet Coordinating Center Duke Clinical Research Institute [name of file], 1

Myths of The Parallel Universe Model: The Site-based Bottleneck in the USA Clinical Practice Clinical Research Higher quality = Higher cost: Larger cohorts Longer follow-up Faster enrollment More site-based burden

Addressing Therapeutic Innovation in the USA R&D Spending & New Rx Applications 10 Year Trends 2004 http://www.fda.gov/oc/initiatives/criticalpath/

2008-2011: The Exodus of Industry & Device Research From the USA The reason, executives say, was that it would take too long to get its new cardiac stent approved by the FDA http://www.nytimes.com/2011/02/10/business/10device.html?_r=1&ref=todayspaper

The TREAT Initiative: Pragmatic Trial Designs for Public Health Issues Cardiac Safety & Bleeding Risk in Women 2010

Study of Access site For Enhancement of PCI for Women SAFE PCI for Women Sponsors*: NIH/NHLBI NCRI grant #: 1RC2HL101512-01 FDA Office of Women s Health Acist Abbot Vascular Eli Lilly Medtronic Terumo *Sponsors: (<20 cents per dollar cost) [name of file], 6

Cath-PCI NCDR sites: SAFE-PCI for Women workflow Randomization Demographics Medical Hx Procedural data 65% site coordinator workload reduction Index Hosp MACE SAFE RCT pts: Autopopulate Part 11 Compliant DCRI DCRI Analytic Database 2.5 unique CRF pages for trial

September 2013 Lauer M et al, NEJM 2013 Hess C et al, Am Heart J 2013 Rao S et al JACC Cardiovascular Int 7(8)2014

SAFE STEMI for Seniors: Linked NCDR-Claims Data Infrastructure: Device rich index hosp & long term follow up NCDR: Index Procedure Long Term Follow-up: CMS: Administrative Claims Data CRF Index data AMI from Clinical Registry Hospitalizatio n 1mo 1 yr 2 yrs 3 yrs 4 yrs 5 yrs Event ascertainment Death, MI, Stroke, Revasc Independent adjudication Months 10

MDRTF Report: August 24, 2015 CRNs: Leverage existing site-based work flow ( dual purpose not doubled work) Leverage EHR/registries implementing structured data No single repository sufficient for device evaluation Strategically linking complementary sources creates sufficiency www.mdepinet.org Krucoff MW, Normand SL et al, JAMA 2015

NEST: The Vision Real World Evidence of Device Benefit/Risk, Safety More real world Less unique effort & cost More value across ecosystem: Regulatory decisions Best practice guidelines Payer decisions Patient information Learning model: Use/re-use structure solutions Linked architecture JAMA Published online July 11, 2016

Registries for embedding trials for regulatory decisions: Transforming real world data into real world evidence Data structure & quality

Disease Specific/Device Specific Data Elements: Defining a Minimum Core Data Set: The RAPID Roadmap CRFs: Pivotal trials Device & procedure Patient variables Device outcomes Clinical outcomes Registries: Best practices Device & procedure Patient variables Clinical outcomes EHRs: Clinical practice Report generators Device & procedure Patient variables Core Min Data Set: Clinical outcomes Common data elements Device non-specific: Pt descriptors Concomitant meds Device specific: Clin presentation Device model, mnfctr Procedural technique Operator training/exp Anatomic features Outcomes Health system workflow Common data model Device specific workflow

Disease Specific/Device Specific Data: Site-based Work Flow EHRs: Procedure reports Outcomes Claims: Coded supplies Coded services Core Minimum Data Set Structure: Enter once/use many Agnostic instantiation Agnostic implementation Transforming RW data into RW evidence Registries: Procedure reports Outcomes Inventory: Supplies Devices Tracking (pts) External data: Other registries Industry sources Etc

RAPID: 21 st Century (NEST) Trial Clinical Operations Model: Prospective RCT Clinical report work flow: Clinical descriptors Device identification Procedural information Outcomes of interest All Pts Electronic record systems: VQI NCDR EPIC Cerner VAMC SIR Part 11 compliant Clinical Trial Database: Clinical descriptors Device identification Procedural information Outcomes of interest Auto Study CRFs Study Pts Structured Core PAD Data Elements Study Site Coordinator Novel Ancillary Study Data (Core Laboratory, QOL)

Impact of consistent data structure over time: Statistical analytics Poolability & meta-analyses Bayesian analytics: exchangeability Longitudinal: generalizability of outcomes Newman AB, Contemporary Clinical Trials 46 (2016) 100 105

Progressive reduction in evidence burden: From one TPLC milestone to the next From breakthrough device to next generation devices Progressive leverage with upstream structured data: Frequentist: poolability, propensity Bayesian: exchangeability

Core Minimum Data Sets & NEST CRN Vision: With a continuous river of structured data you can float a lot of RCT boats If you don t have to re-build the river every single time Traditional Perspective 21 st Century Perspective