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Methodology

Methodology
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Event Classification

Events currently collected in the registry include all events that appear or worsen during the registry and are a result of:

  • Implanted or external components
  • Implant procedure
  • Infusion or stimulation therapy

Information on all deaths is also collected regardless of their relatedness to the device, implant procedure, and/or therapy.

In early versions of the protocol for infusion and spinal cord stimulation systems, an event was reportable only if it required a surgical intervention, led to therapy abandonment, or resulted in death. This event threshold was expanded for infusion and spinal cord stimulation systems in April 2010 in order to capture additional adverse event data.

Additionally, since the protocol expansion, the seriousness (per ISO 14155-1) of adverse events has been assessed and reported by the registry investigators.

For centers participating in the PSR protocol of the registry, specific therapy relevant events are also collected and include:

  • Urinary tract infection for sacral neuromodulation
  • Negative changes in behavior from baseline for deep brain stimulation
  • New or worsening depression from baseline for deep brain stimulation
  • New or worsened suicidal ideation from baseline, attempted suicide or completed suicide for deep brain stimulation

By design, not all adverse events experienced by patients during participation were reported in the registry because the registry is primarily focused on understanding the long term reliability and performance of Medtronic implanted systems.

All events reported in the registry are coded using version 17.0 of the Medical Dictionary for Regulatory Activities (MedDRA). Medtronic's own coding system for events related to implanted neuromodulation systems, which do not exist in the MedDRA dictionary, was integrated with the MedDRA dictionary.

Registry Definitions

Adverse Event - any death or undesirable experience (associated with signs, symptoms, illnesses, or other medical events) occurring to the patient that appears or worsens during the clinical study and is possibly related to the device, implant procedure, and/or therapy.

Device Event - an issue with any of the implantable or external system components.

Therapy Relevant Event - a specific event type for sacral neuromodulation and deep brain stimulation therapies which are collected regardless of relatedness to the device, procedure, or therapy.

 

Adverse Event/Device Event Flowchart
Adverse Event/Device Event Flowchart

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Product-Performance or Non-Product Performance Categorization

For analysis purposes, events collected were collapsed into 2 categories: product performance events and non-product performance events. All events were reviewed by Medtronic to determine if they were product performance-related (product performance events are events that are possibly due to a device-related issue). A non-product performance related event was any undesirable experience (associated with signs, symptoms, illnesses, or other medical events) occurring to the patient, and that appears or worsens during the clinical study, that possibly resulted from or was related to the implant procedure, therapy, or delivery of therapy, and cannot be classified as product performance-related.

Consistency and Accuracy

Consistency and accuracy of event reporting is monitored at four levels: through logic checks built into the study database as center personnel enter information; through review of each event by the study team as it is received by Medtronic; review by the Medical Advisor when necessary; and through routine monitoring at each center per Medtronic standard operating procedures. Monitoring is accomplished through a risk-based approach that aligns with the current FDA guidance on monitoring. Through this approach not every data field is monitored but an emphasis is placed on data related to the primary objective (e.g., events). Clarification and subsequent adjudication of events may be required for, but is not limited to, the following reasons:

  • Inconsistency with the protocols
  • Inconsistency with the instructions provided to the centers through training materials
  • Incomplete or inaccurate event description that makes a reported event reason, event reason detail, and the clinical data appear inadequate or inconsistent
  • Medtronic Customer Support and Vigilance Complaint management requirement for additional information
  • Center personnel initiated corrections or additions

Device Survival Analyses

Device performance is expressed in terms of device survival estimates, where "survival" refers to freedom from a product performance event, not the survival of the patient. These survival probabilities are estimated using the Kaplan-Meier method.1 The estimates are intended to illustrate the probability that a device will survive for a given number of years without a product performance related event.

Active surveillance normally begins at the time of implant and continues until a product performance or censoring event occurs. In some cases in the registry, active surveillance of a device starts after the device was implanted, which is called left truncation.1 The survival probability of such a device is conditional on survival to the time when the device enters the registry. For the PPR analysis, a statistical method to incorporate data from these retrospectively enrolled devices was applied. Left truncation provides a statistical technique that uses data from existing devices while appropriately adjusting the device survival curves for the time the device was not actively followed in the registry. Thus, in some cases sample sizes may fluctuate from one time interval to the next interval.

Throughout this report, cumulative device survival plots are presented. These figures show the percentage of implanted devices that remain free from product performance-related events at various time points. This survival estimate is a good representation of the probability a device will survive a period of time without a product performance event. For example, a device survival probability of 90% indicates that through the stated follow-up time, the device had a 10% risk of incurring a product performance event since the time of implant.

The survival curves are statistical estimates. As performance experience accumulates, the accuracy of the estimation improves. Confidence intervals are provided as a way to indicate the degree of certainty of the estimates. Greenwood's formula is used to calculate the standard errors, and the log-log method is used to produce the 2-sided 95% confidence bounds.2 This can be roughly interpreted as meaning that the true survival of the device will fall somewhere in the interval, with 95% probability. When confidence intervals for device models overlap, estimates of survival from product performance-related events are not different between models. When confidence intervals do not overlap, estimates of survival from product performance-related events are different between models.

The device survival curves are presented through all continuous time points where there are at least 20 devices, and are cut off at the last 3-month time point where at least 20 total devices were still being followed. Since the survival estimate can become very imprecise with small sample sizes, a minimum of 20 devices must have at least 12 months of follow-up as of the report cut-off date to present a survival curve in this report. Device survival estimates are presented at the device level, not at the system level which involves the combination of 2 or more devices.

References
  1. Klein, John P., Moeschberger, Melvin L. Survival Analysis Techniques for Censored and Truncated Data, New York: Springer-Verlag New York, Inc., 1997.
  2. Lee, Elisa T. (2003) Statistical Methods for Survival Data Analysis — 3rd Edition (Wiley Series in Probability and Statistics).

Returned Product Analysis

Registry devices that are returned to Medtronic are analyzed via a Returned Product Analysis (RPA) process following protocols to confirm proper functioning or identification of root cause for any failure or deficiency. For registry pumps and neurostimulators that are returned, and for which RPA establishes a root cause or finds no anomaly, results reported herein reflect the RPA finding unless otherwise indicated in this report. When available, RPA findings are also used as one of the sources to identify the root cause of failure or deficiency for catheters and leads. In cases where the center does not explant and/or return a device, the physician-reported event reason is used for classification and analysis purposes.

Medtronic uses data from RPA as well as complaint reports from non-returned product for ongoing quality monitoring and improvement efforts. This report presents data from the registry including the results of RPA for returned devices from registry centers and patients. Data from RPA outside the registry centers and patients are not presented in this report.

2016 Medtronic Product Performance Report: Data through July 31, 2016.

United States