Published: Jan 22, 2014
By Todd Neale, Senior Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania
Many cardiac implantable electronic device models currently used by clinicians were approved via the pre-market approval supplement process, not as original pre-market approvals.
Most new device models are deemed safe and effective without requiring new clinical data, indicating the importance of post-approval surveillance.
Many of the high-risk implantable cardiac devices in use today were approved through a supplement pathway that does not require new clinical data on the safety and effectiveness of changes made to the products since their original approval, a review of an agency database showed.
From 1979 through 2012, 77 original pre-market approval (PMA) applications -- which required the manufacturers to provide clinical data on the safety and effectiveness of the devices -- were cleared by the FDA, according to Aaron Kesselheim, MD, JD, MPH, of Brigham and Women's Hospital in Boston, and colleagues.
During that same time, however, those original PMAs were subject to 5,829 approved supplement applications, which covered everything from relatively minor changes to labeling, materials, or packaging to substantial design changes, often without the need for additional clinical data, they reported in the Jan. 22/29 issue of the Journal of the American Medical Association.
"It behooves physicians and patients when they're considering a device to understand not only that the device has been FDA approved but to understand the process through which the device was FDA approved and any data that exist about the device," Kesselheim said in an interview.
The FDA uses the PMA process to evaluate new high-risk medical devices, which include pacemakers, implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. But changes to previously approved devices can be introduced using the supplements.
"The benefits [of the supplement pathway] are the more rapid approval and clinical use of new technology," commented Michael Rinaldi, MD, director of clinical research at Carolinas HealthCare System's Sanger Heart & Vascular Institute in Charlotte, N.C., who was not involved in the study. "Requiring a large randomized trial for every proposed iterative device improvement would slow and potentially stop needed improvements in technology."
But it also means that many of the devices clinicians are implanting into patients currently -- which may be substantially different from the device included in the original PMA after numerous small changes -- have not been subject to rigorous clinical testing.
Kesselheim and colleagues noted that the Medtronic Sprint Fidelis and St. Jude Medical Riata ICD leads -- which were recalled in 2007 and 2011, respectively -- were both approved through the supplemental process and were never tested in clinical studies before entering the market.
"The pitfalls [of the supplement pathway] are that it is difficult to know the impact of even seemingly small changes in actual use without clinical data. And as there are usually multiple supplements, many small changes add up," Rita Redberg, MD, of the University of California San Francisco, who co-authored an accompanying editorial, told MedPage Today. "As we learned from the Fidelis and Riata leads, what seems like a good idea may not turn out that way when implanted in patients."
During the study period, there were original PMAs for 46 pacemakers, 19 ICDs, and 12 CRT devices, according to the FDA's PMA database. But each device was subject to a median of 50 supplements (ranging from 0 to 306) by the end of 2012.
The median period of activity for a PMA -- the time from the original approval of the device to the most recent approved supplement -- was 15 years. And more than three-quarters (79%) of the original PMAs approved during the study had at least one supplement approved in the most recent year of the study period.
"The long active life of ... PMA approvals suggests that minor design changes may accumulate over time and in some cases may add up to substantial changes from the device approved in the original PMA application," the authors wrote.
"To guard against this outcome, the FDA could mandate an expert panel review of each PMA every 5 to 7 years in which it is active to evaluate the extent to which clinical data from older models still apply to newer ones," they suggested. "Another possibility would be more widespread implementation of rigorous post-market studies to evaluate device performance once approved for clinical use."
Risk-Benefit Balance of Supplements
The fact that most supplements are approved without additional clinical testing is not necessarily a bad thing, Kesselheim and colleagues wrote, because preclinical testing can be superior in some cases.
"For example, mechanical testing of ICD leads can simulate years of clinical conditions relatively quickly, and animal studies may allow for repeated induction of arrhythmias that would be impossible in a human model," they wrote. "Thus, our results should not be interpreted to indicate that the FDA is failing to review PMA supplement applications to determine safety and effectiveness."
But, preclinical testing may not uncover all of the problems that will occur when the implants are placed in the human body, Redberg and co-author Steven Goodman, MD, PhD, of Stanford University in Stanford, Calif., noted in their editorial.
"The tricky part is that it is hard to know in advance when changes approved by supplements without clinical data will turn out to be dangerous or even life-threatening in clinical use," Redberg told MedPage Today. "This is a particular issue for implanted devices, as they can be risky to remove. One cannot recall implanted medical devices when they are defective, as one does for a car."
The current study does not provide a way to assess the relative risks and benefits of using the supplement pathway to get modified devices approved for use, according to Rinaldi.
"There are risks in over-regulation by slowing useful and clinically beneficial innovation. There are also risks in under-regulation by not detecting well-intended but ultimately harmful innovation," he said. "While the ICD lead recalls were highly visible and clearly harmful to patients, the real question is: how often did rapid approval lead to harm and how often did it lead to benefit and what was the overall magnitude of the harm and benefit?"
He said that FDA is in a difficult position regarding device approvals.
"If they are too conservative, they will slow the pace of improved care and put the U.S. even farther behind other industrialized countries in terms of access to new technology, and they will be criticized by advocates for rapid innovation," he said. "If they are too liberal, then they are at risk for missing problems and will be pilloried by patient safety advocacy groups."
Rinaldi said he thinks the agency does a reasonable job, pointing out that "for all the device changes reported in the article, very few of them have resulted in harm. While the ICD lead problems are used to illustrate the downside of less strict regulation, no examples are provided of how patients were helped by iterative advances through this process or harmed by lack of access to improvements."
Kesselheim is supported by a Robert Wood Johnson Foundation Investigator Award in Health Policy Research, a Greenwall Faculty Scholarship in Bioethics, and a career development award from the Agency for Healthcare Research and Quality. One of his co-authors was supported by a Harvard Medical School fellowship. Another is the Lois Green Scholar at the Hebrew SeniorLife Institute for Aging Research and is supported by a career development award from the Harvard Catalyst Clinical and Translational Research Center and a Paul B. Beeson career development award in aging.
Kesselheim and one of his co-authors reported previously publishing research funded by the FDA on comparative medical device regulation. That co-author reported serving as a consultant to the FDA's Circulatory Systems Advisory Panel.
Redberg reported being a member of the FDA's Circulatory System Devices Panel and a member of the California Technology Assessment Forum. She is the editor of JAMA Internal Medicine. Goodman did not report any conflicts of interest.
From the American Heart Association:
Primary source: Journal of the American Medical Association Source reference: Rome B, et al "FDA approval of cardiac implantable electronic devices via original and supplement premarket approval pathways, 1979-2012" JAMA 2014; 311: 385-391.
Additional source: Journal of the American Medical Association Source reference:Goodman S, Redberg R "Opening the FDA black box" JAMA 2014; 311: 361-363.