Download - 1st CUTEHeart Workshop Resnic Presentation
03-02-2015
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Frederic S. Resnic, MD MScChairman, Department of Cardiovascular Medicine Co‐Director, Comparative Effectiveness Research InstituteLahey Clinic Medical Center Tufts University School of Medicine
Post‐Market Safety Surveillance for Medical Devices
November, 2014
Medical Device Post Approval Safety
• Challenges and Current Approaches for Post-Market Safety Assurance of Medical Devices
• Limitations of Claims-based safety surveillance for medical devices.
• FDA Roadmap for Improving Post-Market Safety Assurance – UDI and Registries
• Active Surveillance – Example of Prospective national surveillance
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Key Differences Between Drugs and Medical Devices for Safety Surveillance
Resnic FS
Medications:• Exposure: NDC uniform
documentation for inpatient/outpatient
• Available in claims records
• Pharmacy benefits DB• Often suitable for
population based surveillance
Devices:• Exposure: Previously: no
uniform documentation. Today: requirement for UDI.
• Variable documentation of implant procedure
• Multiple failure modes • Rapid Iteration / Life Cycle• Learning curve: device vs.
procedural quality
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Registries for Methodology Development:Device Learning Curve
Source: Resnic FS et al. JACC Interventions Jan 2012
An evaluation of 107,000 consecutive new VCD deployments in the national NCDR CathPCI dataset demonstrates a clear learning curve in the use of these devices.
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Adverse Event Reporting Today• Primary responsibility of healthcare facilities to
report medical device failures and complications to manufacturers. Must report all related deaths.• FDA receives >300,000 MDR reports per year• GAO estimates <0.5% events reported
• Major Failures of Adverse Reporting Today:• No “denominator” information• Poor quality reports; 50% without specific device
information.
• MedSun Network facilitates bi-directional communication between selected facilities and CDRH
Device Safety Data SourcesAdministrative Claims Data
Registries (Condition, Procedure, etc.)
Advantages
Disadvantages
• Large, representative population
• Longitudinal outcomes ascertainment
• Standardized coding schemes
• Limited clinical granularity (limits risk adjustment)
• Lack of specific device identification
• Data quality ~ billing requirements
• Temporal availability of data.
• Detailed clinical information
• Device exposure detailed information
• Only available for select medical devices
• Variable data quality• Limited, selected
populations• Limited longitudinal
outcome ascertainment• Data access and
ownership restrictions• Cost to maintain
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FDA Sentinel Program
Source: Mini-Sentinel Update – ISPE August 2011
FDA Sentinel Program
Adapted from: Platt R. et al. Pharmacoepi Drug Safety 2012
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FDA Sentinel Program• Data sources are “augmented administrative claims” databases
• Seeks to include outpatient pharmacy dispensing• Claims defined utilization: encounters, procedures,
diagnoses• Common data model with distributed queries where source
information is maintained behind data owner’s firewall.
• Currently >140 million persons included; 40 million with 3+ years worth of data. 316 million person-yrs data.• 30 million medication dispenses per month• 400K hospitalizations per month. • Dataset updated quarterly.
Source: Mini-Sentinel Update – ISPE August 2011
FDA Sentinel Program: Example
Source: Platt R. Mini-Sentinel Update – ISPE August 2011
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Claims‐based Device Safety Surveillance
• Very (very) few examples of using administrative claims datasets in isolation for device safety surveillance.• Limited by lack of specific device identification• No Sentinel based device surveillance to date.
• One study based on fortunate circumstance of unique ICD-9 code for Drug Eluting Stents (vs. BMS) using IV analysis.
Source: Federspiel et al. Am Heart J. 2012
FDA RoadmapRecommendations:
1. Establish Unique Device Identifier System
2. Promote National and International Registries for selected devices
3. Modernize Adverse Event Reporting Systems
4. Develop new methods for evidence generation, synthesis and appraisal.
5. Established MDEpiNet –Public Private Partnership
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CV Device Registry Quality vs .Cost
Higher CostData Quality
Lower Cost Lower Quality
Single CenterVoluntary
Multi-CenterVoluntary
NationalVoluntary
RegionalMandatory
UniversalMandatory
Duke DatabaseBrigham Many others
Northern New EnglandICD Consortium
NCDR: PCI, CAS
MA PCINY PCI
InterMACSTVT
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Regional Mandatory Registries: Audited, Adjudicated and Linked
Patient Cohort
• 6 million residents
• 14 centers perform 7,200 open heart surgeries per year
• 21 centers perform 16,000 coronary intervention (stent) procedures per year
Massachusetts DPH implemented mandatory clinical outcomes registries for invasive cardiac services in 2002, focused on monitoring the performance of hospitals and physicians.
Dataset Features
• Standardized definitions (STS, NCDR)
• Rigorous adjudication and audits
• Linked outcomes to vital statistics and inpatient claims data
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Linked Claims and Device Dataset
Source: Bangalore S. et al – Cath Cardiovasc Interv 2014
Linked MA Angioplasty dataset with inpatient claims file to identify all patients who had non-cardiac surgery within 12 months of stent implantation. Propensity matched BMS to DES
UDI Status and Opportunities
• Two Components: • UDI – Model/type code + Specific Lot/serial number• Global UDI Database – maintained at FDA. Reference listing of devices and characteristics.
• Final rule issues in September 2013, with implementation schedule: • New Class III devices establish code in September, 2014, but actual labeling by 2015.
• 2016 for existing Class III devices• Uncertainty into whether UDI will be required in claims or EHR data flows. Awaiting CMS, ONC and private payor decisions.
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Active Surveillance Steps:
Adapted from: Platt R. et al. Pharmacoepi Drug Safety 2012
Step 1: Step 2: Step 3:
Active Surveillance: Complementing Existing Safety Monitoring
Event Reporting
Active Surveillance
MandatedStudies
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Active Surveillance: Complementing Existing Safety Monitoring
Event Reporting
Active Surveillance
MandatedStudies
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• Use clinical datasets to optimize analyses to identify potential safety signals through multiple, concurrent, continuous and prospective adjusted safety surveillance analyses.
• Value is in detection of low frequency safety signals earlier than traditional retrospective studies. Focus limited analyst resources on prospectively defined safety risk alerts.
• Always hypothesis generating – requiring further epidemiologic exploration and validation• Unmeasured confounders in underlying datasets.• Inherent device safety vs. procedure quality
uncertainty
Principles of Active Medical Device Safety Surveillance
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22Adapted from: Resnic F et al. JAMA November 2010
Using the MA state-wide PCI device dataset, we explored the cumulativepost-procedure myocardial infarction rate for new drug eluting stent as compared with propensity matched control DES.
Using 38 clinical variables in propensity match a total of 81.5% of 18,277 new stents were analyzed.
MA Experience 2004-2007: Post Procedure MI Rates – Taxus Express vs. Cypher DES
DELTA Automated Surveillance: Retrospective Cohort Registry Analysis
Cumulative use of Taxus Stent
Taxus Stent Rate of MI
Comparator DES 95% CI of risk of MI
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23Adapted from: Resnic F et al. JAMA November 2010
DELTA Automated Surveillance: Retrospective Cohort Registry Analysis
Propensity matching selected as primary analysis as a strategy to reduce treatment selection bias based on ability to communicate to public and policy makers.
24Hauser et al. Circ Cardiovasc Qual Outcomes. 2012
Using pooled data from three high volume centers, DELTA performed a propensity matched analysis 0f 859 Fidelis lead implants versus traditional leads. By 25 months of analysis (dashed line) 3% of Fidelis leads had fractured (red line) whereas only 0.1% (1 of 859) alternative ICD leads had fractured.
Voluntary Recall
DELTA Automated Surveillance: Hospital Registries and Time Savings
Quattro
FidelisPotential TimeSavings
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CathPCI DELTA Pilot Project
• Implemented DELTA within NCDR. Secure IT infrastructure, all data stays within NCDR firewall.
• Primary Analyses: • Vascular complications with Mynx VCD compared with other VCDs [Safety Concern]
• Safety of Thrombectomy devices used during PCI. [Negative Control].
• Prospective, Propensity matched comparison, with sensitivity analyses (LR) if alert fires.
• Predefined high risk patient subset analyses.• Post‐Hoc exploration: Time to first safety alert; Simplified attempt to adjust for treatment selection bias.
Prior Investigation: VCD and CathPCI
Tavris et al. J Invas Card. July 2012
Exploration of over 1.8 million PCI cases in CathPCI between 2005 and 2009 and found that VCD’s had lower risk adjusted adverse event rates as compared with manual compresion. However, there was a safety signal for increased risk with the Mynx device.
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Preliminary Results: Export ATCPrimary endpoint: Propensity Matched Analysis of the incidence of death following use of Export family aspiration thrombectomy catheter versus other aspiration thrombectomy catheters
27Preliminary Analysis: NCDR CathPCI DELTA Pilot Project – 11-2014
Preliminary Results: Mynx VCDPropensity Matched Analysis of the incidence of “any vascular complication” following use of Mynx family closure device versus other active VCD demonstrated a RR of 1.68 for Mynx.
Preliminary Analysis: NCDR CathPCI DELTA Pilot Project – 11-2014
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Triggered Sensitivity AnalysisProtocol mandated confirmation of any alert through separate Logistic Regression analysis. It has been frequently observed that LR adjustment leads to greater differences in performance, as compared with PS.
Preliminary Analysis: NCDR CathPCI DELTA Pilot Project – 01-2014
Mynx VCD: Subgroup Analysis Pre‐specified subgroup analysis was performed for high risk subgroups including: women, the age>70 and patients with diabetes.
Preliminary Analysis: NCDR CathPCI DELTA Pilot Project – 11-2014
Female Patients Age > 70yr
Diabetic Patients
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Exploring Time to First AlertGiven the early alert identified, data from 2009‐2010 was added retrospectively. The first alert for Any Vascular Complication signaled after the 2nd Quarter of data with less than 10,000 exposures documented.
Preliminary Analysis: NCDR CathPCI DELTA Pilot Project – 11-2014
Exploring Treatment Selection BiasWhen restricted to those centers that used Mynx VCD with the highest frequency, the observed difference in vascular complications was significantly attenuated (RR=1.36), but still higher than “high utilizers” of alternative VCD.
Preliminary Analysis: NCDR CathPCI DELTA Pilot Project – 11-2014
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Future DELTA Monitoring Projects
• Utilizing same DELTA hardware and software within secure NCDR network:
– ICD Registry pilot – comparison of propensity matched freedom from lead revision for 3 commonly used ICD leads
– Proposed TVT monitoring pilot –comparison of 12 month safety of Sapien vs. CoreValve for high risk and for inoperable patient cohorts.
• Prespecified analytic plans, with escalation protocol for any potential safety signals. Proposal to involve manufacturers in surveillance protocol development and signal verification process.
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Conclusions
• Traditional spontaneous adverse event reports have significant value (unexpected associations), and will continue to play a key role in safety surveillance for medical devices.
• Full implementation of UDI (with data flow through EHR and Claims) will enable powerful “Big Data” exploration of medical device performance.
• Active Surveillance is can be used as a near real‐time approach to fill gaps in current safety net by monitoring clinical datasets (device registries) for low frequency safety signals. • Must consider any alert as “hypothesis generating” requiring additional epidemiologic exploration and verification.
• MDEpiNet collaborative will help lead the field, identify best practices, establish best methods, develop risk communication strategies, and bring multiple stakeholders together.
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Thank You!! Lahey Clinic Medical Center
Susan RobbinsHenry Sessamaga, MD
Harvard Medical School
Sharon-Lise Normand, PhD
Vanderbilt University VAMC
Michael Matheny, MD MSc MPH USCD NCBC
Lucila Ohno-Machado, MD PhD
FDA CDRH
Danica Marinac-Dabic, MD PhD
Boston Advanced Analytics
Richard Cope
For more information contact: [email protected]
Entire NCDR Technical StaffKathleen Hewitt
Idealized Safety Monitoring System
Data Source
Data Source
Data Source
Data Source
Monitoring System
Distributed Data Ownership
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Idealized Safety Monitoring System
Data Source
Data Source
Data Source
Data Source
Monitoring System
Distributed Data Ownership
Alerts
Reports
Expectation andRisk Adjustment
Safety Analyst
Monitoring System
• Continuously updated• Array of statistical analytic
options• Monitor multiple analyses
simultaneously • Flexible Alert notification • Generic structure• Widely accessible – feedback
to source sites
Monitoring System
• Continuously updated• Array of statistical analytic
options• Monitor multiple analyses
simultaneously • Flexible Alert notification • Generic structure• Widely accessible – feedback
to source sites
38DELTA Program – Submitted for publication
Mynx VCD was associated with a non-statistical trend toward increased vascular complications and transfusions following use. While the relative risk was 2.20 (95% CI: 0.71-6.3), the sample size of patients receiving Mynx was small.
DELTA Network 2008-2012: Mynx VCD Usage Trends
DELTA Automated Surveillance: Prospective Distributed Registry Analysis
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Device Registries
Advantages Limitations•Real world experience; safety and efficacy outcomes
• Depth of clinical data available for adjustment
•Product specific device identification
• Utilization patterns – permits evaluation of denominator and therefore event rates
•Potential for use in PAS (INTERMACS, ICD, TAVR)
•Flexible to permit sub-analyses and hypothesis generating explorations
• Assurance of data quality (voluntary registries)
• Limited number of endpoints• Limited longitudinal followup• Potential but Challenges Mapping
to claims databases• Costly to maintain• Many/Most devices do not have
adequate registries in 2011
Adapted From: Marinac-Dabic M. CDRH Post-Market Update
Sentinel Initiative• In response to HHS directive, IOM report on drug safety risks
(2006), program launched in 2007 in an effort to develop a national electronic system to monitor medical product safety.• Intended to complement passive adverse event reporting
systems • Codified in FDAAA section 905: Goal of 100MM patient
records by 7/1/12• Focus on access to information, tools to analyze data, and
data standards. • Features of “Sentinel System”:
• Distributed data systems – data maintained by owners• Support targeted queries rapidly; with varying detail• Minimal transfer of data (avoid case level information)
Source: Qato D and Alexander GC. JAMA 2011