PPR overview and methodology

Medtronic uses a prospective, long-term multi-center registry to monitor the performance of certain products at selected centers titled the Product Surveillance Registry (PSR). This registry was initially created by Medtronic to monitor the performance of commercially available target drug delivery (TDD) and spinal cord stimulation (PSTM) systems. Later on deep brain stimulation (DBS) and sacral neuromodulation (SNM) were added to the registry. This 2021 Product Performance Report (PPR) provides data on the devices followed in the registry. Medtronic also incorporates the findings of Returned Product Analysis (RPA) for devices followed in the registry that are returned to Medtronic.
 

Depending upon geography, this report may contain information outside approved labeling for the Medtronic commercially available devices. It is recognized that healthcare providers prescribe approved therapies to meet specific patient needs; however, Medtronic only directs the use of its products according to geography-specific, approved labeling.
 

The registry has collected data from centers across North America, Europe, South America, and Asia. There have been 76 centers that have contributed data for TDD systems, 84 centers for PSTM systems, 51 centers for DBS systems, and 24 centers for SNM systems. Each registry center received Institutional Review Board or Medical Ethics Committee approval of the registry protocol and associated Informed Consent Forms (ICF). Registry patients signed an ICF prior to enrollment. Each registry center followed its standard clinical practice for device system implantation including patient selection, implant methods, and post-implant therapy management. Centers were activated after receipt of the necessary documentation, completion of training, and approval to access the web-based registry system. 

The Medtronic commitment to quality has long been stated in our Mission, “To strive without reserve for the greatest possible reliability and quality in our products; to be the unsurpassed standard of comparison and to be recognized as a company of dedication, honesty, integrity, and service.”
 

In line with this commitment we remain focused on sharing information and appropriate updates with customers on a regular basis. Thus, we are pleased to share the 14th Annual Medtronic Neuromodulation Product Performance Report.
 

We are proud of our pioneering history at Medtronic and we realize the responsibility that comes with driving innovation in technology. As the first and only company to offer a full line of Spinal Cord Stimulation, Deep Brain Stimulation, Sacral Neuromodulation and Targeted Drug Delivery therapies, we believe that performance reporting is of critical importance as we strive for better performance with every new product and therapy we develop. This report shows the evolution of product performance over time and also reveals advances in therapies that come with this experience and knowledge. Through this sharing of information we can enable physicians to best leverage state-of-the-art therapy delivery and also understand the performance of our devices to best manage patients.
 

We have tracked 20,225 patients in our ongoing post-market registry. The registry has enrolled 62,196 Neuromodulation system components. Components include pumps, catheters, neurostimulators, leads, and extensions. Data on other events not directly attributed to product performance are also included to provide additional information that may be important for patient management. Although gastric electrical stimulation also involves neurostimulation, the performance of these systems is not included in this report.
 

We welcome your suggestions on content, format, and any information you may have regarding the performance of Medtronic products. If you have questions or comments, please contact us through the information provided below.
 

Thank you for your support.
 

Todd Weaver, PhD, MPH
Senior Clinical Research Manager, Post-Approval Clinical Surveillance
Clinical Research, Medical Science and Regulatory Affairs (CMRA)

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 (device related),
• Implant or modification procedure (procedure related), or
• Infusion or stimulation therapy (therapy related).

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

For centers participating in the PSR protocol, specific therapy relevant events for deep brain stimulation are also collected and include:

• Negative changes in behavior from baseline,
• New or worsening depression from baseline, and
• New or worsened suicidal ideation from baseline, attempted suicide or completed suicide.

For some events related to implanted neuromodulation systems that did not exist in the MedDRA dictionary, Medtronic used their own coding system, and all results were integrated for reporting purposes.
 

Registry definitions

In the registry, the events are defined as follows (see Figure 2.1 for the procedure to detemine the event types):

• 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, 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 deep brain stimulation therapies which are collected regardless of relatedness to the device, procedure, or therapy.

Product performance and non-product performance categorization

For analysis purposes, events collected were collapsed into two 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, or a clinical event not related to product performance, 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. These clinical events not related to product performance possibly resulted from or were related to the implant procedure, or modification between implant and procedure, therapy, or delivery of therapy, and cannot be classified as product performance-related. All clinical events not related to a product performance and reported as a serious adverse event were summarized by MedDRA System Organ Class (SOC) if the event met a patient percentage threshold (0.5% to 1.0%).

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, or
• Center personnel initiated corrections or additions.

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 may not be different between models. When confidence intervals do not overlap, estimates of survival from product performance-related events may be different between models. Statistical significance may be further evaluated using the Log-rank test or Wilcoxon test as appropriate.
 

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 two or more devices.
 

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).