Clinical Electrophysiology and Medical Devices: The Role of the FDA

In a typical hospital on any given day, physicians, nurses, patients, and their families are affected by the regulatory activities of the U.S. Food and Drug Administration (FDA). From making new technologies and drugs available to allowing the conduction of clinical studies of investigational products, from monitoring adverse event reports to overseeing the conduct of product recalls, the FDA’s regulatory activities impact patients and clinicians. Nowhere is this more apparent than in the electrophysiology (EP) lab, where new medical technologies are adopted readily, and where the treatment of patients involves life-saving, state-of-the-art medical devices. The FDA’s Center for Devices and Radiological Health (CDRH) is the entity responsible for the regulation of medical devices from premarket to postmarket. Within CDRH, the Cardiac EP Network is the community of staff and managers dedicated to ensuring a coordinated approach to the regulation of pacemakers, defibrillators, cardiac ablation systems, electrophysiology diagnostic tools, and cardiac monitoring systems. This article discusses how the FDA’s responsibilities are carried out by members of the Cardiac EP Network. Product Approvals On February 6, 2009, the FDA announced the approval of the NaviStar® ThermoCool® irrigated diagnostic and ablation catheter (Biosense Webster, Inc., a Johnson & Johnson company, Diamond Bar, CA), the first such system approved for the treatment of drug-refractory recurrent symptomatic paroxysmal atrial fibrillation.1 Product approvals are probably the most visible regulatory responsibility of the FDA, giving clinicians access to new diagnostic and treatment options for patients. In CDRH’s Cardiac EP Network, about 30 premarket reviewers and managers are responsible for processing nearly 1,600 premarket applications every year. These include not only applications for new product approvals, but also requests to begin clinical trials (called Investigational Device Exemptions, or IDEs), annual reports, and requests for early interactions with the FDA (called pre-IDEs). As a framework for premarket review, the FDA established a classification system that allows for graded premarket requirements depending on the level of risk posed by the device. The lowest risk device types, designated Class I, are exempt from having to undergo a premarket review by the FDA, while higher risk devices either have to show substantial equivalence to marketed products (Class II) or establish a reasonable assurance of safety and effectiveness (Class III). FDA scientists, engineers and clinicians take into consideration all the testing provided by the manufacturer to qualify the device’s safety and effectiveness. This might include mechanical, electrical, and biocompatibility testing, animal testing, sterilization and packaging evaluation. The manufacturer may also need to submit an IDE in order to request FDA approval to begin studying an investigational device in human clinical trials. The results of the clinical trial will appear in the device labeling as a summary of the product’s safety and effectiveness. For a first-of-its-kind device, the FDA may call on its independent advisory committee to provide recommendations to the agency, as was done for Biosense Webster’s NaviStar® system. The Circulatory System Devices Panel assessed the results of the 167-patient clinical trial showing that the device was effective in eliminating symptomatic recurrence of atrial fibrillation episodes for one year in approximately 63% of patients versus 17% of the patients in the control group, and unanimously recommended approval.1 Adverse Event Reporting and Postmarket Surveillance Once devices are on the market, the FDA monitors their performance in the real-world setting using a variety of approaches, including evaluating individual adverse event reports, post-approval study results, and annual reports submitted by manufacturers. Medical Device Reporting is the provision of the law that puts adverse event reporting requirements on medical device manufacturers, importers, and user facilities (e.g., hospitals, nursing homes, etc.). These reports are reviewed and monitored by FDA staff who perform surveillance for unexpected device-related events and emerging trends that may reveal performance concerns. A handful of nurses and engineers in CDRH’s Cardiac EP Network are responsible for examining the more than 30,000 individual reports of malfunctions, serious injuries and deaths submitted each year for pacemakers, ICDs, AEDs, ablation systems, and cardiac monitors. In the past year, members of the Cardiac EP Network have been following trends in ICD lead perforations2 and monitoring system alarms,3 to name just two. The FDA requires manufacturers to have complaint handling processes in place to receive, process, and take action on adverse event reports. In addition, they must submit adverse event reports to the FDA in order to be compliant with the regulations. However, reporting of adverse events often begins with the clinicians who use the devices and encounter real or potential risks to their patients. In a demanding EP clinic, it can be difficult enough to stay on top of patient management without the added burden of having to formally “diagnose,” document, and report device malfunctions. And yet, without this first step, neither the manufacturer nor the FDA can develop a complete picture of device performance. Postmarket surveillance can prove particularly challenging for many medical devices seen in the EP setting. Clinicians may blame a problem with an arrhythmia monitor on user error, not appreciating that many such reports highlight design and labeling problems that can be corrected. Likewise, many clinicians may not submit reports of pacemaker and ICD lead failures because they are unsure which abnormal lead behaviors may potentially be design-related (such as dislodgement and perforation). These challenges were discussed at an FDA workshop in 2008 that brought together regulators, clinicians, and industry.4 A number of best practices for clinicians were identified, as noted in Table 1. As a general rule, clinicians are encouraged to report adverse events associated with medical devices to the manufacturer or directly to the FDA so that the process of surveillance can begin. Reporting device-related adverse events directly to the FDA can be done online at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm. Device Recalls On June 11, 2009, the FDA announced the recall of a subset of Kappa and Sigma pacemakers (Medtronic, Minneapolis, MN).5 The pacemakers were prone to a specific failure mode involving separation of the internal wires, resulting in a loss of rate response, premature battery depletion, loss of telemetry, or no output. The FDA has specific responsibilities in the event of a voluntary device recall such as this.6 The FDA oversees each recall to make sure that the actions the company takes are adequate to protect public health. During a medical device recall, the FDA: • works with the recalling firm to obtain information about the product, the problem, the recall strategy, and the steps to prevent the problem from happening again; • evaluates risk information and classifies the recall in Class I, II, and III, from most serious to less serious; • receives and evaluates periodic reports on the recall, and determines when it is complete for termination; • conducts audits to make sure the recall efforts are appropriate and effective; • makes sure the company takes necessary actions to prevent the problem from happening again.6 One of the more common complaints the FDA hears from the EP community is the challenge of managing product recalls, particularly for implanted devices such as pacemakers and ICDs. EP staff must grapple with practical considerations, such as identifying patients affected by the recall and scheduling them to come in for follow-up visits. They also have to deal with the very real anxieties felt by patients and their families upon hearing they have an implanted device that is subject to a recall.7,8 For many people, the word “recall” is misinterpreted as a call for explantation and removal of an implanted device. For the FDA, the term “recall” applies to situations where the firm stops distributing a device and pulls back products from distribution, or when the firm institutes a correction to the products already in distribution.6 Corrections might include re-labeling equipment, providing new instructions for use, installing corrective software patches, or monitoring patients more closely. And while there have been no pacemaker or ICD recalls where the clinical recommendation involved prophylactic explantation of the device, clinicians are still faced with having to decide on a case-by-case basis what is best for an individual patient with a device under recall. In 2007, members of CDRH’s Cardiac EP Network developed guidelines to help industry provide physicians with information relevant to patient management of ICD recalls.9 Healthcare professionals can use the FDA’s online recall database to learn about current and past medical device recalls: www.fda.gov/MedicalDevices/Safety/RecallsCorrectionsRemovals/ListofRecalls/default.htm. Risk Communication and Transparency On February 28-29, 2008, the FDA convened the first meeting of its newly-formed Risk Communication Advisory Committee, a group charged with understanding how the public receives information about FDA-regulated products and how the FDA can best reach consumers, patients and physicians. The committee has met regularly since then to tackle issues such as direct-to-consumer marketing of pharmaceuticals and how to communicate emerging or uncertain risks, culminating in the development of a strategic plan for risk communication.10 CDRH’s Cardiac EP Network is more specifically interested in how clinicians and patients perceive messages about cardiac EP devices. Toward this end, risk communication specialists in CDRH’s Cardiac EP Network conducted focus group sessions with electrophysiologists, EP staff, caregivers and patients with pacemakers and ICDs to understand their needs for communication from the FDA, particularly around product recalls. They also performed media analyses to see how messages about cardiac EP products are presented to the public. As part of the Center’s day-to-day operations, these specialists are responsible for developing communication strategies by working with technical staff to identify the intended audiences, develop key messages, and determine the best vehicle for communication. Science and Research at the FDA It is a common — but mistaken — notion that CDRH makes its premarket approval decisions based on a physical evaluation of the device. Distinct from its premarket reviewers, CDRH has in-house scientists and engineers whose mission is to explore broad public health problems related to medical devices and cross-cutting technological issues. For example, recently scientists in CDRH completed results of research showing the effect of radiofrequency identification (RFID) systems on implanted pacemakers and ICDs.11 Their evaluation showed that some models of RFID readers could interfere with pacemaker and ICD functions, causing a range of responses including inappropriate tachyarrhythmia detection, pacing inhibition, and inappropriate pacing. Researchers in the Cardiac EP Network are also exploring the interactions of drugs and devices,12 and developing methods to test new defibrillation waveforms.13 Summary While the work of the FDA may not be on the minds of clinicians or patients on any given day in a busy EP clinic, chances are the next medical device they reach for will have some connection to the FDA. Clinicians should know that there are dedicated nurses, scientists, engineers and physicians in the FDA’s Cardiac EP Network who share their passion for the patients, and for the safety and effectiveness of medical devices. For more information, please visit: https://www.fda.gov/