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
Action Points
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."
The Study
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.
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