1st CUTEHeart Workshop Resnic Presentation

03-02-2015

1

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

03-02-2015

2

3

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

4

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.

03-02-2015

3

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

03-02-2015

4

FDA Sentinel Program

Source: Mini-Sentinel Update – ISPE August 2011

FDA Sentinel Program

Adapted from: Platt R. et al. Pharmacoepi Drug Safety 2012

03-02-2015

5

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

03-02-2015

6

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

03-02-2015

7

13

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

14

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

03-02-2015

8

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.

03-02-2015

9

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

03-02-2015

10

Active Surveillance: Complementing Existing Safety Monitoring

Event Reporting

Active Surveillance

MandatedStudies

20

• 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

03-02-2015

11

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

03-02-2015

12

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

03-02-2015

13

25

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.

03-02-2015

14

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

03-02-2015

15

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.


Mynx VCD: Subgroup Analysis Pre‐specified subgroup analysis was performed for high risk subgroups including: women, the age>70 and patients with diabetes.


Female Patients Age > 70yr

Diabetic Patients

03-02-2015

16

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.


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.


03-02-2015

17

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.

34

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.

03-02-2015

18

35

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

03-02-2015

19

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

03-02-2015

20

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

Education

1st CUTEHeart Workshop Resnic Presentation