The Device Makers’ Shortcut
A few years
ago, the Food and Drug Administration announced a stunning
recall, saying that electrical wires in some St. Jude Medical heart defibrillators,
which were implanted in tens of thousands of people, were defective. It was a
rerun for cardiac patients: In 2007, Medtronic recalled its Sprint Fidelis
cardiac devices because of
faulty wires.
In both cases, the F.D.A. warned
that the wires could
cause painful shocks or fail when needed, and patients were
left to choose between living with the leads under close monitoring
or having dangerous surgery to replace them. Both companies reported deaths
linked to the flawed leads.
Now a new paper by Harvard researchers, using records only recently
made available by the F.D.A., explains how the faulty leads got onto the
market, shedding light on a little-known process used by manufacturers to alter medical devices without
putting them through human trials. (An
approval pathway for lower-risk medical devices, called the 510(k) clearance,
has received more public scrutiny, including harsh criticism
from the Institute of Medicine.)
For so-called high-risk devices
like heart defibrillators, the F.D.A. typically requires proof of safety and
effectiveness in clinical trials with real patients under real-life conditions.
But once such a device
receives initial approval, the researchers found, an administrative maneuver
permits companies to tinker with it — making the electrical wire
thinner, for example — without
testing the changes in a single patient.
The process, called a premarket approval supplement
application, allows manufacturers to get upgrades and improvements to patients
faster, medical device companies say. The application is “intended for a change
to an already approved P.M.A. that has met the agency’s rigorous requirements
for safety and effectiveness,” said Janet Trunzo, senior executive vice
president for technology and regulatory affairs with AdvaMed, a trade association. She noted that
the F.D.A. could require a more rigorous review process if necessary.
The problem is that a device can be modified over
and over, even dozens of times, without ever being put through new
trials in patients. From 1979 and 2012, the researchers found, the F.D.A.
approved 77 new cardiac-implanted electronic devices like pacemakers and
defibrillators. During that same period, the agency approved nearly 6,000
supplement applications.
A spokesman for Medtronic said the
company did test the
Sprint Fidelis’s new leads in patients, but the trials were begun in
November 2003, around the time the company also filed its
supplement applications, and the resulting data were not shared with
the F.D.A. before the thinner leads went on the market. The study was published
only in 2007, shortly before the recall.
For each device that went through the full premarket approval process,
50 subsequent changes were made, researchers also found.
“Over time, the accumulation of changes may lead to a device
that is substantially different than the original product,” said Dr. Aaron S. Kesselheim, senior
author of the paper,
published in JAMA, the
journal of the American Medical Association.
“Most of top-selling devices that are out on the market now have all
been approved via supplements for the last 10 years,” he said. They are
“substantially different” from the versions originally approved, he said.
While some of the supplement
changes were minor, like rewriting instructions or changing the color, 37
percent involved a change to the device’s design, Dr. Kesselheim and his
colleagues said. Companies
are not required to mention the changes on the package labels, and generally do
not.
As a result, doctors are often unaware which
version of the device they are implanting, said Dr. Rita Redberg, a
cardiologist and professor at University of California, San Francisco, who has written on
the topic. “These supplements are not just flying under patients’
radar screens, they’re flying under doctors’ radar screens,” Dr. Redberg said.
The recalled wire in St. Jude’s
defibrillator was approved as a supplement to a device whose original design
had been approved in 1996 but had undergone 78 supplementary revisions,
according to the research. The
recalled Sprint Fidelis lead was approved as a supplement to a device
originally approved in 1993 and modified 91 times.
“These leads may have worked in the lab, but that is very different from
what happens inside a human blood vessel,” Dr. Redberg
said. “People move around, they’re very complex, and the lead is going to be
exposed to a lot more stress and forces of resistance.”
Clinical trials don’t always find
rare complications. But the
failure rate in St. Jude’s device was high enough that it would have been
noticed in a trial, she said.
The pace of supplements has
increased significantly during the past decade, to 704 a year from 77, the
researchers found. The
last time an implantable cardioverter defibrillator went through a full
rigorous premarket approval process was in 2000, the researchers said,
“indicating that all models released since then have been supplements” to
existing models.
But since a Supreme Court decision in 2008 determined that
manufacturers were immune from liability for personal injuries as long as their
devices had been approved by the F.D.A., injured patients who want to sue face an uphill
battle. Dr. Kesselheim and his colleagues
put forth several proposals
in their article, suggesting
the F.D.A. convene a panel of experts to review approved medical devices every
five to seven years and determine whether the clinical data from the older
models still applied to the newer versions.
But the agency appears to have rejected
the idea. An automatic advisory panel review is not “a necessary or
efficient use of F.D.A. or taxpayer resources,” said Susan Laine, a
spokeswoman.
The JAMA article concludes by highlighting the
importance of rigorous post-market data gathering to bolster the FDA assurance
of ‘safe and effective’. This
could be done by PCORI (Patient Centered Outcome Research Institute) which is a
new government non-profit agency commissioned and funded by Congress. However, though the omission of
implanted medical device patient outcomes research has been demanded by harmed
patient and patient advocates, PCORI has resolutely avoided this
responsibility. http://www.americanprogress.org/events/2014/01/16/82429/high-priced-drugs-and-medical-devices/
Aaron Seth Kesselheim M.D., J.D.,
M.P.H.
Assistant Professor
Department of Medicine
Harvard Medical School
Email: akesselheim@partners.org
Discipline: Medicine, Drug Development, Law
Investigator Award
Award Year: 2009
How can the engine of pharmaceutical innovation in
the United States, sluggish now despite substantial investment, be jump-started
again? Whether the right pathway involves increased government support of basic
research or a transformation of industry product development and clinical trial
work, patent law will play a key role. Aaron S. Kesselheim, M.D., J.D., M.P.H.,
explores a number of questions related to this issue, including how basic,
translational, and product-development research combine to create breakthrough
drugs and how patent-based incentives facilitate or impede drug development.
His project, Sources of Transformative Innovation in Medication Development,
will identify the most transformative drugs that have emerged in the past 25
years, examine their scientific origins, and assess the intellectual, social,
and financial factors that influenced their development. Dr. Kesselheim also
will analyze whether
patents have rewarded the most important contributors to new pharmaceutical
breakthrough products and test an alternative to the current patent system. His
project addresses whether new legal or resource-allocation strategies are
needed to reinvigorate pharmaceutical innovation and how possible reforms might
encourage drug development, apportion rewards more appropriately, and help
contain research costs.
Background
Aaron S. Kesselheim is an assistant professor of
medicine at Harvard Medical School, based in the division of
pharmacoepidemiology and pharmacoeconomics, department of medicine, Brigham and
Women?s Hospital (BWH). He graduated from Harvard College and received his
postgraduate training at the University of Pennsylvania School of Medicine and
Law School, and most recently at the Harvard School of Public Health. He is board-certified in
internal medicine, serves as a primary care physician, and attends on the
general medicine inpatient service at BWH. He is a member of the New York State
Bar and is a patent attorney. His research focuses on the effects of
intellectual property laws and regulatory policies on pharmaceutical
development, the drug approval process, and the costs, availability, and use of
prescription drugs both domestically and in resource-poor settings. He received a career development
award from the Agency for Healthcare Research and Quality to study comparative
evidence, regulation, and trends related to prescribing off-label drugs.
He has contributed commissioned works on market-based incentives for
pharmaceutical R&D to the Institute of Medicine and the Robert Wood Johnson
Public Health Law Research Program. He has also investigated other issues at
the intersection of law
and public health, including health care fraud, expert testimony in malpractice
cases, and insurance reimbursement practices. His numerous articles and
book chapters related to these topics have appeared in leading medical and
health policy journals, including the New England Journal of Medicine, JAMA, and Health
Affairs. In 2010,
he received the Alice S. Hersh New Investigator Award from AcademyHealth, the
main professional organization for health services/policy research. The
Hersh award is given annually to an outstanding health services researcher
under age 40 in the U.S. In addition to his research, Dr. Kesselheim has taught
on law and public health issues at Harvard Medical School, Law School, and the
School of Public Health. He has testified before the U.S. House of Representatives and addressed
different state legislatures on drug policy matters, and he has consulted for the federal
government?s clinical trials registration website (ClinicalTrials.gov). He has
also served as an ad hoc peer reviewer for numerous medical and scientific
journals (earning a commendation for his work from Annals of Internal
Medicine in 2009), the Harvard Law Review, and the London School of Economics.
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Many cardiac devices approved by
process that often does not require new clinical data
Date:
January 21, 2014
Source:
The JAMA Network Journals
Summary:
Many cardiac implantable
electronic device models currently in use were approved via a Food and Drug
Administration review process in which the models were assumed safe and
effective based on approval of prior versions of the device, according to a
study.
Many cardiac implantable
electronic device models currently in use were approved via a Food and Drug
Administration review process in which the models were assumed safe and
effective based on approval of prior versions of the device, according to a
study in the January 22/29 issue of JAMA.
"In the United States, the
Food and Drug Administration (FDA) reviews high-risk medical devices -- those
that support human life, prevent illness, or present an unreasonable risk --
via the premarket approval (PMA) pathway, through which manufacturers collect
preclinical and clinical data as necessary to provide 'reasonable assurance' of
the device's safety and effectiveness," according to background
information in the article. That process has attracted attention in recent
years after recall of device components, like leads from Medtronic Sprint
Fidelis and St. Jude Medical Riata implantable cardioverter-defibrillators
(ICDs), that were not tested clinically in human trials prior to approval
because they were design changes to prior-marketed devices and considered
'supplements' to PMA applications submitted almost a decade earlier.
The process of approval by
premarket approval supplement "allow[s] patients to benefit from
incremental innovation in device technology by providing efficient and
inexpensive FDA review pathways for smaller device changes. Supplements may
include major or minor design changes as well as routine changes in labeling,
materials, or packaging. By statute, the FDA must seek only the 'least
burdensome' supporting data necessary for review."
Benjamin N. Rome, B.A., of Harvard
Medical School and Brigham and Women's Hospital, Boston, and colleagues used
the FDA's PMA database to review CIEDs (including pacemakers, ICDs, and cardiac
resynchronization therapy [CRT] devices) approved as PMA supplements from 1979
through 2012. They identified the number of supplements to each original PMA
and characterized the nature of the changes in each supplement.
Seventy-seven approved PMA
applications for CIEDs (46 pacemaker devices, 19 ICDs, and 12 CRT devices) were
the basis for 5,829 PMA supplement applications, with a median (midpoint) of 50
supplements per original PMA. In the last decade, the number of approved
supplements annually increased to 704. Excluding manufacturing changes that do
not alter device design, the number of supplements approved each year averaged
2.6 per PMA per year.
Thirty-seven percent of
supplements represented at least minor alterations to the device's design or
materials. Among 180-day supplements (a type of FDA review process) approved
between 2010 and 2012, 23 percent included new clinical data to support safety
and effectiveness.
"… Our results should not be interpreted to indicate that the FDA
is failing to review PMA supplement applications to determine safety and
effectiveness," the authors conclude. However, clinicians and patients
should … be aware … that clinical data are rarely collected as part of PMA
supplement applications prior to marketing. The
recalled Medtronic Sprint Fidelis and St. Jude Riata ICD leads were both PMA
supplements -- Fidelis a 180-day supplement and Riata a real-time supplement [a
type of FDA review process]. Neither lead was studied in human trials prior to
FDA approval. The FDA's approval of many supplements without new human trials,
as in the case of these recent ICD changes, highlights the importance of collecting rigorous
postapproval performance data," the authors write.
Story Source:
The above story is based on materials provided by The JAMA Network Journals. Note: Materials may be
edited for content and length.
Journal Reference:
Benjamin N. Rome, Daniel B.
Kramer, Aaron S. Kesselheim. FDA Approval of Cardiac Implantable Electronic
Devices via Original and Supplement Premarket Approval Pathways, 1979-2012.
JAMA, 2014; 311 (4): 385 DOI: 10.1001/jama.2013.284986
Cite This Page:
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The JAMA Network Journals.
"Many cardiac devices approved by process that often does not require new
clinical data." ScienceDaily. ScienceDaily, 21 January 2014.
<www.sciencedaily.com/releases/2014/01/140121164748.htm>.
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