The FDA’s Circulatory System Devices Panel recommended that an implantable cardiac monitor that alerts patients to ST-segment shifts, an indicator of coronary ischemia, should not be approved for use in patients who are at risk for recurrent coronary events.
The panel voted 4-8 that the Guardian System (Angel Medical Systems, Inc.) is safe, 0-12 that it is effective and 0-12 that its benefits outweigh its risks.
Panel member Scott R. Evans, PhD, from the Harvard School of Public Health, who voted no to all three questions, said that “although safety endpoints were met, that didn’t equate to the safety question.” He said he was also concerned about quality issues with the data presented.
“Although the technology is promising, the totality of evidence didn’t support a yes answer to any of the three questions,” said panel member Kristen K. Patton, MD, from the University of Washington.
Angel Medical Systems, manufacturer of the implantable cardiac monitor, is seeking approval for an indication to alert patients to ST-segment changes with the intention to shorten the time-to-door from detection to arrival at the hospital.
If approved, the Guardian System would be the first monitoring system to alert patients to a coronary event independent of recognizable symptoms.
The sponsor is seeking approval based on the results of the ALERTS study, in which the monitor system met the primary safety endpoint of greater than 90% rate of freedom from system-related complications, but not the primary efficacy endpoint, which was a composite of late arrival (>2 hours) after a confirmed coronary artery occlusion event, new Q wave, and cardiac or unexplained death.
Of the 1,020 patients originally enrolled, 907 patients were randomized 1:1 to either the treatment group where the alert system was turned on or the control group where it was turned off. Of those 907 patients, 271 of them experienced 364 adverse events (129 control, 136 treatment and 6 non-randomized). Thirty patients (3.3%) had 31 events related to system complications. This 96.7% event-free rate had a posterior probability of event reduction greater than 0.9999.
When using the 7-day maximum for late arrivals, the posterior probability of superiority was 0.7856 (rate of primary endpoint events, 3.8% for treatment group vs. 4.9% for control group). The posterior probability of superiority, however, increased to 0.974 (rate of primary endpoint events, 3.8% for treatment group vs. 6.8% for control group) when the look-back window was changed to 90-day maximum for late arrivals. In the treatment group, 179 alarms were reported, but 40% of them were excluded from the analysis.
Zhiheng Xu, PhD, a biostatistician in the division of biostatistics, office of surveillance and biometrics for FDA said during the FDA’s presentation, “the sponsor’s decision to stop enrollment is viewed by FDA as a significant protocol violation. The validity of the trial may be undermined from a compliance, data quality and trial integrity perspective.”
According to the FDA documents, “the composite primary effectiveness endpoint presents some challenges in determining the device’s effectiveness to detect ischemic events, particularly with respect to the time-to-door and the new Q wave endpoints.”
“The quality of the ECG data and the inconsistency of the Q wave results caused the sponsor to terminate the study earlier than the protocol required, and to institute a dual baseline approach with serial reads to the ECG interpretation,” the FDA staff wrote.
According to the documents, another concern with the validity of the study was that the added look-back windows were not adjusted for in the primary effectiveness analysis which “could lead to false declaration of significance and therefore spurious inference.”
If the device is approved, Angel Medical Systems has agreed to limit device distribution to those sites who had participated in the ALERTS study and have agreed to be a part of the postmarket study.
Panel member Lori E. Dodd, PhD, from the National Institute of Allergy and Infectious Diseases, said after the vote, “I was very moved by the patient testimony, but ultimately, the question of endpoint definitions is concerning.”
The FDA is not required to follow the recommendations of its advisory panels, but it usually does. – by Tracey Romero
Reference: Circulatory System Devices Panel Clinical Briefing Document P150009.
Disclosure: The members of the Circulatory System Devices Panel report no relevant financial disclosures.