Premarketing approval of cardiovascular devices by the Food and Drug Administration often rests on a very shaky foundation, according to a review of 123 studies.
Most of the clinical studies the FDA has relied on to approve CV devices are neither blinded nor randomized. About half are not controlled or use only historical controls, which produces biased results favoring the devices, the study investigators reported. In addition, most of the studies exclude data on patients who have unfavorable outcomes; and are performed in subjects who are not representative of the patient populations that will be using the devices.
Moreover, the majority of such FDA approvals have rested on the results of a single study, reported Dr. Sanket S. Dhruva and associates at the University of California, San Francisco (JAMA 2009;302:2679–85).
The public assumes that the FDA's premarketing approval “is the most rigorous device approval process, and strict standards for cardiovascular devices are expected given their far-reaching effects, permanent nature, and use in critically ill patients.” Yet the type and quality of the evidence on which the FDA bases its approval have never been systematically examined until now, the investigators noted.
They reviewed the 123 clinical studies underlying FDA approval of 78 cardiovascular devices between 2000 and 2007.
The mean number of studies supporting each approval was only 1.6; fully 65% of the device approvals were supported by only a single study.
Most approvals did not cite even one blinded or one randomized study. Overall, only 27% of the supporting studies were randomized and only 14% were blinded.
Nearly half of the studies supporting FDA approval failed to include a control group for comparison. Of those that did include a control group, retrospectively selected controls were commonly used, which biases the results in favor of the device, the authors wrote.
Many studies excluded data from lead-in periods, which effectively excludes subjects who have immediate unfavorable outcomes. Most also showed large discrepancies between the number of subjects enrolled and the number included in final analyses, with no explanation of the missing data.
In all, data on 10,352 study subjects were excluded, which constitutes nearly a third of the total study population. Twenty percent of the studies did not even report the number of subjects participating.
In more than one-third of the device approvals, “we were not able to ascertain that even 1 study had been conducted in the United States. This results in uncertain generalizability of approved medical devices to the US population,” Dr. Dhruva and associates said.
In addition, many devices were approved “using a post hoc analysis of data,” which can bias the results in favor of the device, they said.
“The importance of the 'seal of FDA approval' cannot be overstated. Many manufacturers immediately encourage widespread use of their devices based on FDA approval through direct-to-consumer advertising, detailing to physicians, and continuing medical education venues,” the investigators noted.
The findings of this study are particularly disturbing given that FDA device approval effectively preempts consumers from bringing lawsuits because of problems with device safety or effectiveness. Moreover, manufacturers are not required to seek out and report device malfunctions, “so device-related adverse events are substantially underreported,” they said.
The investigators noted that a limitation of the study may be that the data source is primarily publicly available summaries of safety and effectiveness data.
Disclosures: Dr. Dhruva's associate in this study, Dr. Rita Redberg, reported being a member of the FDA Circulatory System Devices Panel and a member of the California Technology Assessment Forum. No other potential conflicts were reported.