Posted 16 March 2017
By Michael Mezher
The UK's Medicines and Healthcare products Regulatory Agency's expert advisory group on leadless cardiac devices has released its initial recommendations for pre- and postmarket clinical studies for leadless pacemakers.
According to MHRA, leadless pacemakers, which do not rely on wired leads to deliver a signal to the heart, have the potential to significantly benefit patients, as the most common adverse events caused by implanted cardiac devices involve the leads.
"These complications include lead fracture, insulation failure, and infection. Removal and replacement of chronically implanted pacing and especially defibrillation leads can be a major undertaking. Furthermore, trans venous pacing is sometimes difficult or impossible due to occlusion of great veins; and coronary venous anatomy sometimes precludes adequate transvenous cardiac resynchronization," MHRA writes.
To date, three leadless pacemakers have received CE marking: St. Jude Medical's Nanostim, Medtronic's Micra and EBR Systems' Wireless Cardiac Stimulation system (WiCS), only one of which, Medtronic's Micra has been approved in the US.
However, MHRA says that so far the clinical data supporting the use of leadless pacemakers is limited, both in terms of study size and follow-up duration, noting differences in the requirements for CE marking versus premarket approval by the US Food and Drug Administration.
Because studies to support CE marking are typically small in size, MHRA says it is critical for device makers to minimize bias and to agree upon study design with regulators before conducting the study.
"Such studies can, at best, explore adverse event rates associated with short or medium-term implant durations. Therefore, they should, except in exceptional circumstances, be supplemented by [post market clinical follow-up] PMCF studies or registries to evaluate the longer-term safety and performance," MHRA writes.
According to MHRA, sponsors should plan their studies around the anticipated frequency and seriousness of adverse events in both the pre- and postmarket setting.
"Patient numbers should enable an adequately powered comparison with established adverse event rates associated with clinical alternatives," MHRA writes.
To determine how many patients will be necessary for pre- and postmarket studies, MHRA has included a table detailing the recommended sample size and confidence intervals for different adverse event frequencies.
"For pre-market studies, wider confidence intervals and lower power may be acceptable in order to achieve a compromise between adequate assessment of short and medium-term device safety and the avoidance of undue delay in patient access to the novel treatment. For PMCF studies or registries, greater confidence in the accuracy of the study results is essential, leading to the need to select a sample size achieving results with narrower confidence intervals and greater power," MHRA writes.