The Device Makers’ Shortcut
By RONI CARYN RABIN MARCH 31, 2014, 4:31 PM 16 Comments
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.
Aaron Seth Kesselheim M.D., J.D., M.P.H.
Department of Medicine
Harvard Medical School
Discipline: Medicine, Drug Development, Law
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.
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
January 21, 2014
The JAMA Network Journals
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.
The above story is based on materials provided by The JAMA Network Journals. Note: Materials may be edited for content and length.
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
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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>.