The Root Causes of Harm From Medical Devices
The FDA Office of Criminal Investigations is being asked to determine why the agency has failed to detect the upstaging of cancers in women who had been operated on with a power morcellator.
These devices, widely used to shred uterine tissue in minimally invasive gynecological surgery, are now known to upstage undetected cancers that, according to FDA, occur in one of about 350 patients undergoing hysterectomies and myomectomies.
It took over two decades for the agency to realize that thousands of women may have died from metastatic uterine sarcoma upstaged by power morcellators, Rep. Mike Fitzpatrick (R-Pa.) wrote in a Dec. 18 letter to the agency.
“For over two decades since the power morcellator was cleared for use on patients, the FDA’s Medical Device Reporting regulations failed to catch the severe dangers posed to women’s health by morcellation,” Fitzpatrick wrote. “It appears that these patient safety regulations may not be working as intended, leaving patients in danger.”
The letter includes 26 questions concerning possible failures to report adverse events at Brigham & Women’s Hospital, Rochester General Hospital, University of Rochester Medical Center, and Johnson & Johnson subsidiary Ethicon, the largest manufacturer of power morcellators.
“It should not have taken a family devastated by this device to raise the issue to the FDA,” wrote Fitzpatrick, the House member who represents Hooman Noorchashm and Amy Reed, the physician couple who first focused the attention of the public on the hazards of power morcellators.
Fitzpatrick’s letter can be downloaded here.
Fitzpatrick joins the FBI and the Government Accountability Office, which have launched separate investigations posing similar questions to FDA, device manufacturers and hospitals nationwide.
“FDA cannot comment on any planned or ongoing investigations,” an agency spokesperson said to The Cancer Letter.
Over 300 patients and families have come forward claiming harm, and at least 50 lawsuits have been filed. Critics say the press has overblown the issue, causing a knee-jerk reaction on the part of the agency, which led to restrictions and black box warnings on the use of power morcellators. As a result of an FDA guidance published in November 2014, women are now getting more invasive surgeries. (The Cancer Letter, November 26, 2014.)
In a two-year investigation, The Cancer Letter found that patients aren’t always told that they have been harmed by medical devices. Though federal statutes require hospitals and manufacturers to report adverse outcomes to the agency, no such reports were filed until Reed and Noorchashm’s Medical Device Report in December 2013. Reed’s undetected sarcoma was upstaged during power morcellation at Brigham and Women’s Hospital two months earlier.
Experts on FDA regulation point to flaws in the system for regulation of medical devices and the agency’s implementation of existing laws:
• Bill Vodra, a former FDA associate chief counsel for drugs, says that the agency’s Class II 510(k) clearance process for medium-risk devices—a category that includes the power morcellator—is inadequate, because it does not focus on risk assessment. Instead, the process relies on “substantial equivalence” to predicate devices, thereby allowing subsequent iterations of a device to introduce risk without active FDA surveillance.
• Larry Pilot, one of the original authors of the 510(k) legislation, says that patients are being harmed because FDA doesn’t commit sufficient resources to enforce federal requirements for hospitals and manufacturers to report adverse outcomes caused by medical devices. Pilot said the agency has the authority to demand more robust data when clearing power morcellators for the market.
• Gregory Daniel, fellow and managing director of the Center for Health Policy at the Brookings Institution, says that devices aren’t tracked with the same rigor as drugs. FDA does not have a data system that can reliably track medical devices and identify potential safety problems. A good postmarket surveillance system would pick up signals of harm through claims data and electronic health records, thereby reducing the need to rely on reporting of serious adverse events.
A Clash Over Standards
As is the case with FDA laws, regulations and guidances, the standards for clearance and approval of devices are often disputed.
FDA uses a three-tier classification process for medical devices. Class I includes devices with the lowest risk, such as elastic bandages and examination gloves. Class II devices are cleared through the 510(k) process, which applies to new devices that are based on comparability to devices already in use. Power morcellators were placed into this category.
Only Class III high-risk devices require an FDA premarket approval application. These include pacemakers and HIV diagnostic tests.
The vast majority of devices go through the 510(k) process—about 3,900 Class II devices were cleared for the market in fiscal 2013. By comparison, only about 45 devices are approved every year through the Class III premarket approval process.
The power morcellator is a good example of how the 510(k) process fails to protect the American public, said Bill Vodra, a retired partner at the Washington, D.C., law firm Arnold and Porter.
“The current test for clearance of a 510(k) is, ‘Is the proposed device substantially equivalent to another device—the predicate device or device chain—that has been marketed?’ The answer may be yes, but that does not tell you much about risk of the proposed device or its predicates,” Vodra said to The Cancer Letter. “For a comprehensive evaluation of the 510(k) process, see the Institute of Medicine report in 2011. The whole premise of the IOM criticism was, if FDA doesn’t ask about the risks, it’s not necessarily going to get answers about risk.”
The 2011 report, titled “Medical Devices and the Public’s Health: The FDA 510(k) Clearance Process at 35 Years,” was authored by an IOM committee asked by FDA and Congress to review the legislation in 2009.
Vodra helped draft many agency regulations still in use, including those implementing the Controlled Substances Act and FDA’s rules for Good Manufacturing Practices, Good Laboratory Practices, Good Clinical Practices, bioequivalency and the Orange Book.
FDA should revamp the 510(k) process to categorize devices into several risk-based groups, Vodra said. This could allow for differentiation of surgical tools like power morcellators from products like acupuncture needles.
“You start by having a question in the preclearance process: what do we know about the risk posed by this device and its predicates?” Vodra said. “That could mean breaking apart the current Class II devices into a much larger universe of disparate device groups, because different groups of devices present risks similar to each other, but distinct from other groups of devices.”
A conversation with Vodra is posted here.
FDA disagrees with the IOM recommendation to splinter Class II devices into multiple categories.
“While FDA does not agree with IOM’s recommendation to create a new system, we do believe that we can make improvements to the current system and we have worked to do so over the past four years,” Dayle Cristinzio, acting associate commissioner for legislation at FDA, wrote in a Nov. 12 letter to Fitzpatrick.
“FDA believes that for certain medical devices, comparison to a predicate device is an efficient and scientifically sound method of product evaluations. Tens of thousands of medical devices cleared through the 510(k) program function well for U.S. patients.”
Risk shouldn’t be used as the sole classifier, said Larry Pilot, one of the original authors of the 510(k) process.
Devices shouldn’t be classified according to the risk they pose, because the legislation was designed to provide “reasonable assurance” of safety and effectiveness—a higher threshold than “risk,” Pilot said to The Cancer Letter.
“I disagree with the agency’s position and in particular, the IOM on the characterization of the classification process as risk-based,” Pilot said. “It is not risk-based, and I have said this many times, because the criteria that applied to each one of the three classes was in the context of reasonable assurance of safety and effectiveness.
“A subset of safety is risk, yes, but this low, medium and high risk is fabrication.
“The statutory language, which didn’t change, is quite clear that it is about safety and effectiveness, whereas functionally—if people want to look at risk—it’s inappropriate for the agency to use risk as a surrogate for the explanation, when safety and effectiveness are the criteria.
“For drugs, it’s absolute safety and effectiveness, whereas in the statute applicable to devices, it’s reasonable assurance. That was a distinction that was made during the legislative process, because the objective was to avoid pigeonholing this industry into the criteria that applied to drugs.”
A conversation with Pilot is posted here.
Pilot: Enforcement Needed at User Facilities
There is no need to revamp the 510(k) process, Pilot said. The agency should instead enforce existing laws to make device manufacturers and user facilities report adverse outcomes.
“It’s a good system we have now, but FDA needs to allocate more resources to enforcement, especially for user facilities,” Pilot said. “That’s why FDA, with its authority, and this opportunity to put the emphasis on reporting to the user facility required by law, and then by specific regulation, should be going for money penalties for user facilities that do not abide by the reporting requirement.
“I know for almost 10 years, many user facilities have not been keeping records, and did not have the required written procedures for evaluating whether a complaint justified an MDR.
“And FDA didn’t know that? They haven’t looked at any of this? How has FDA been managing what these user facilities are doing? What has the agency been doing?
“Because people like Amy [Reed] are being hurt by this. If she knew that it was, instead of one in 10,000, a one in 300 chance, she’d probably say no. This is an embarrassment to the agency.
“Going back to the responsibility of the external community, the users and manufacturers—I expect the FDA to have done a better job.”
According to FDA, failure to comply with medical device reporting requirements will render a device “misbranded,” and may result in the issuance of a warning letter or more severe penalties such as seizure of the device or monetary penalties.
In FDA’s letter to Rep. Fitzpatrick, Criztinzio said that the agency generally focuses its enforcement on manufacturers, and not on user facilities.
“We have found that encouraging more reporting—and more complete reporting—by user facilities is a good use of our limited resources in this area,” Criztinzio wrote.
Pilot said he is “astounded” by Criztinzio’s letter.
“What? That surprises me, because I believe too much of the agency’s resources go to manufacturers and are wasteful,” Pilot said. “Encourage? I could never write a letter like that to Congress.
“That letter must have passed through [FDA Center for Devices and Radiological Health Director Jeffrey] Shuren’s office. He had to have seen that letter that says, ‘Oh, we have a voluntary system for the user facility community, but with the industry, we have a mandatory system.’ You’ve got to be kidding me.
“This kind of judgment or failure to exercise judgment has been harmful to the agency and more importantly, to the public. This is our world—FDA’s world—and we need to at least have some minimal understanding of surveillance, or when it’s important to step up surveillance.
“If Brigham at Harvard isn’t reporting, what about other groups and other user facilities?”
Vodra said that adverse outcomes reports are “extremely difficult to identify, capture, investigate and interpret.”
“That’s why I’m not so judgmental, off the top of my head, that a company should or should not have reported a medical problem until I know the facts of a particular case,” Vodra said.
However, in the 2006 whistleblower case involving Johnson & Johnson subsidiary Ethicon, the reporting of a power morcellation near-miss case should have led to warnings, additional research, and to discussions with FDA, Vodra said (The Cancer Letter, Nov. 20).
“The near-miss case [reported by Robert Lamparter, a retired pathologist from central Pennsylvania] should probably have led a manufacturer to reassess the potential risks,” Vodra said. “I’m not giving the company a full pass.”
FDA: We Are Not Aware of Criminal Prosecutions
FDA officials say the agency has investigated cases of failure to report and taken enforcement actions.
“But we are not aware of criminal prosecutions that have resulted from a failure to report adverse events,” FDA said in a statement to The Cancer Letter.
The most recent example of prosecution for failure to submit reports to FDA was the TMJ Implants case involving joint prostheses. This case is referenced in the draft guidance titled “Medical Device Reporting for Manufacturers,” dated July 9, 2013.
A summary of the outcome noted: “One court agreed that although some of these consequences may be deemed clinically insignificant, they are considered to be serious injuries when coupled with the interventions, e.g. administration of antibiotics or other medications, explant, reconstruction, debridement, or revision surgery.” (TMJ Implants, Inc. v. U.S. Department of Health & Human Services, 2009.)
In another 2009 case, the FDA issued warning letters to 17 LASIK ambulatory surgical centers after inspections revealed inadequate adverse event reporting systems at all the centers. Under adverse outcomes reporting legislation passed in 1990, user facilities are required to have a written protocol for adverse event reporting.
The inspections did not identify problems with the use of the LASIK devices—which permanently change the shape of the cornea with laser—at these facilities.
“FDA has an active industry training program, consisting of presentations, webinars, and numerous web resources,” an FDA spokesperson said. “We also receive and address hundreds of questions from industry each year related to what should be reported and how to report.
“Congress recognized the challenges of user facility reporting and in the 1997 FDA Modernization Act provided FDA with the opportunity to design and implement a national surveillance network composed of well-trained clinical facilities that can provide high-quality data on medical devices in clinical use.”
According to FDA, about 250 hospitals participate in the Medical Product Safety Network—also known as the MedSun program—which provides webinars, presentations, online trainings, and videos.
“Such tools help hospitals understand how identifying and reporting device problems to FDA early on can impact public health and improve patient safety in their hospitals,” FDA said. “These facilities are trained to not only submit reports required by the MDR regulations but also to submit ‘potential for harm’ events that would otherwise be considered voluntary reports to FDA.
“We are also currently working with 20 hospitals from our MedSun Network to develop software capabilities to export real-time adverse event data with device identifiers from hospital incident reporting systems. The ASTER study demonstrated that facilitated ‘triggered reporting’ increased the number of adverse events reported by clinicians.
“The FDA has taken a number of recent steps to modernize the adverse event reporting and analysis systems including the development of automated adverse event reporting systems. We are also working to increase the number of reports submitted electronically with a goal of reaching an electronic submission rate of 95 percent of all reports submitted.”
Daniel: No Reliable Data System for Tracking Devices in U.S.
Experts say devices aren’t tracked with the same rigor as drugs, because FDA doesn’t have a reliable medical device tracking system analogous to the National Drug Code Directory, which assigns unique identifiers to each drug product.
“On the drug side, the NDCs are great, because they are ubiquitous in electronic health data,” said Daniel, fellow and managing director of the Center for Health Policy at Brookings. “NDCs are included in claims data, they’re included in electronic medical records, and because of that, it’s very efficient to go to large claims data sources in electronic medical records and quickly identify unique drug exposures and then link those exposure to outcomes.
“That doesn’t exist on the device side,” Daniel said to The Cancer Letter. “Unique device identifiers did not exist—but now the system exists, but the challenge is that just having the identifier on the device itself doesn’t help us better identify devices in the electronic health care data systems.”
A conversation with Daniel is posted here.
FDA is working on improving its postmarket surveillance system for devices in collaboration with Brookings—an effort that Daniel said would reduce reliance on spontaneous reporting of adverse outcomes.
The initiative, called the National Medical Device Postmarket Surveillance System, or MDS, will use unique device identifiers, insurance claims data and electronic medical records to create a database that can track devices and link them with patient outcomes.
“I think that the major impetus [for this program] is a realization that there isn’t at all an existing sustainable data system in the United States that one can use to track and understand how medical devices are performing across different patient populations, across clinical settings,” Daniel said.
“First, without having such a data system that can be used for active safety surveillance—i.e., safety monitoring that doesn’t rely on reporting of adverse events by providers or manufacturers—it is challenging to quickly identify potential safety issues with devices early on.
“Second, without such a system, it is very costly and resource-intensive to develop longer term evidence on the effectiveness and impact on patient outcomes of medical devices. Better systems for developing evidence on safety and effectiveness could also help support innovation through enabling more streamlined and routine data collection that would be required for regulatory decisions.”
The MDS is at least five years away from full deployment. The new system should eventually make it easier for FDA and other stakeholders to pick up adverse outcomes resulting from medical devices such as the power morcellator, Daniel said.
“Generally, I think it is safe to say that with better, more robust postmarket surveillance that the MDS can provide, certainly in a lot of cases, this would enable the accumulation of evidence on the devices much more rapidly and in much larger populations than is currently available right now,” Daniel said.
“You get a better understanding of what’s happening sooner. If there is a safety issue that’s happening out there, this would improve the accumulation of evidence in terms of speed and quantity.
“Also, the system will not rely on reporting of serious adverse events as the data that will be leveraged will automatically include them as they are identified from claims, EHRs, and registries, not on spontaneous report data.”
Before the MDS can work, stakeholders need to invest in systems for documenting and reporting unique device identifiers, Daniels said.
“Providers, payers, patients need to use the UDIs and document them, mostly on the provider and payer side into the electronic medical record in the claims data in order to be able to much more efficiently identify unique devices in the data themselves.
“So the NDC is a good example on the drug side of how that can be done. We do have tremendous amounts of drug safety surveillance, comparative effectiveness research, quality reporting, etc.—and we learn a lot about drugs, not only initially when the drugs are on the market, but drugs that have been on the market for 10, 20 years. We have a wealth of data available to really understand how that drug performs in a variety of different patient populations, thanks to the ubiquitous nature of the NDC.
“We’d like to be able to get there on the device side, but it will take a lot of investment up front by payers, providers, and hospitals to develop the data capability and infrastructure to be able to document and report those UDIs in the claims in the electronic medical records.”
With a system like the MDS, medical device registries will become obsolete, Vodra said.
“I don’t see any major improvements in the voluntary self-reporting system that will vastly improve our ability to detect and fix problems, though I hope that some of the initiatives underway at FDA and in the medical community will make a difference,” Vodra said. “Voluntary reporting remains valuable for providing insight. The guy who says ‘I think this may be a problem’ often has thought long and hard about it, and has generated a hypothesis.”
To test this hypothesis, the medical device community needs to move from the current system to a Big Data network, where one can process vast amounts of claims data and link it up with specific devices, Vodra said.
“Instead of going to the spontaneous reporting database, FDA can go to claims data and say, ‘Let’s run this through the computer and get results,’” Vodra said. “If there is upstaging of cancer, and if this is more commonly associated with use of a particular drug or device over others, you should be able to see these trends more rapidly because you have a huge amount of data.
“From 2015 to 2025, I would argue that Big Data is the way we’re going to head.”