Millions of Americans take blood thinners like Coumadin and Jantoven (brand names for warfarin) to prevent blood clots that could cause a heart attack, stroke or other medical problems. But it is critical that the blood is not thinned too much, creating a risk of internal bleeding, or thinned too little, increasing the risk of a blood clot. Point-of-care (POC) medical devices, known as prothrombin time (PT) test devices, such as the Alere INRatio monitor, were designed to measure blood clotting time outside of a medical laboratory and help patients maintain their blood in an optimum therapeutic state.
Recently, however, many consumers have filed lawsuits charging that two of those devices, the Alere INRatio and/or Alere INRatio2 monitors, were defective, producing inaccurate clotting time results that placed the lives of device users at risk. Their complaints, as well as the thousands of adverse event reports on the devices compiled by the U.S. Food and Drug Administration (FDA), were the driving force behind a “public workshop” held by the FDA on March 18, 2016, in Silver Spring, Maryland, to address the safety and accuracy of POC PT test devices.
“CDHR [FDA’s Center for Devices and Radiological Health] should consider removing the INRatio device from the market.”
– Sydney Wolfe, MD, Director, Public Citizen Health Research Group, testimony at the FDA Workshop on Point of Care Prothrombin Time/International Normalized Ratio Devices for Monitoring Warfarin Therapy, March 18, 2016.
The workshop received little coverage in the media, though a recent review of the workshop transcripts and presentation slides revealed a number of startling facts about the devices and produced some surprising admissions from FDA scientists. The agency clearly felt a need to do much more to protect consumers from devices that may put the health and lives of those who take blood thinners at risk.
The workshop’s first speaker was Dr. Alberto Gutierrez, director of the FDA’s Office of In Vitro Diagnostics and Radiological Health (OIR). The OIR is within the FDA’s Center for Radiological Health, which is tasked with regulating in-home and laboratory diagnostics tests. Its job, according to the OIR website, is to “assure that patients have access to safe, effective and high quality medical devices and prevent the marketing of unsafe or ineffective devices.”
Gutierrez began by acknowledging that devices like the Alere INRatio are “difficult devices.” Laboratory devices, he noted, “tend to be more accurate and more reproducible.” POC devices, on the other hand, “are what they are,” he said. Gutierrez also observed that the people who use such devices are “fairly sick.”
Given these concerns, one would expect that such devices undergo rigorous testing before receiving FDA approval to insure their results are accurate. But Dr. Gutierrez suggested this was not the case. “When,” he asked, “do you decide the accuracy and the precision of the device is good enough without really having the ability to ask for major clinical trials or the ability to determine how well the device works?”
When the head of the FDA office charged with insuring medical devices are safe acknowledges that POC devices are “difficult’ and the FDA has no actual ability to determine how well a device works, there is definite cause for concern. Unfortunately, the next speaker, Lea Carrington, director of OIR’s Division of Immunology and Hematology Devices, did not provide any reassurance. Ms. Carrington disclosed that the high number of medical device malfunction reports the FDA had received had caused them to “reassess the safety of these devices and consider how well current review requirements demonstrate the actual real world performance characteristics” of point-of-care blood coagulation time meters.
Actual real world performance appears to be highly variable. Dr. Rong Rong, a medical officer in the OIR’s Division of Immunology and Hematology Devices, testified that there is often “clinically important discrepancy” between the INR values (a measure of how “thick or thin” the blood is) obtained using point-of-care devices and laboratory testing. Making this finding more problematic is the fact that the “likelihood to see such discrepancy increases as the INR increase[s].” In other words, as the blood becomes thinner and the danger of internal bleeding increases, INR readings from point-of-care devices are increasingly likely to differ from more reliable lab tests.
As an example, Dr. Rong described the case of a patient whose POC test, performed by an experienced nurse who was well trained on a PT test device, indicated that the patient’s blood was in an optimum range (INR of 2.4. The range of 2.0 to 3.0 is ideal for most indications.). The patient ultimately was hospitalized, where a lab test showed an INR of 9.1. The patient died of gastrointestinal bleeding.
Later in the workshop, Dr. Michael Streiff, Medical Director of the Johns Hopkins Hospital Special Coagulation Laboratory, described the process by which Johns Hopkins chose the brand of POC PT test device it would use. The hospital compared readings on two brands of devices (neither was an Alere INRatio) against lab readings. They tested about 100 patients with this question in mind: Were the POC device and lab INR readings so dissimilar that clinicians, relying on the POC device reading, would have made a different medical decision had they relied instead on the lab reading?
The readings from one brand of device differed from the lab reading enough that it would have caused clinicians to make different medical decisions 30% of the time. The other brand, that figure was 18%. Needless to say, Johns Hopkins chose the brand that would have resulted in altered medical treatment only 18% of the time. But both results suggested that even with the best devices, nearly one in five INR readings may be significantly in error.
FDA Approval Process for Alere INRatio Skips Clinical Trials
Part of the problem lies in the FDA’s 510(k) approval process. The agency allows medical device makers to bypass clinical trials and win approval by demonstrating that a new device is “substantially equivalent” to a device that is already on the market, called the “predicate device.”
But what if there is a problem with the predicate device? The FDA collects reports on malfunctions, injuries and deaths tied to medical devices in its MAUDE (Manufacturer and User Facility Device Experience) database. What if hundreds of such reports associated with a predicate device have been filed with the FDA? Would that prevent the device from being cleared for use? Oddly enough, the answer appears to be “No.”
For example, the INRatio2 PT Monitoring System (made by Hemosense, a company Alere bought in August 2007) was approved by the FDA on October 26, 2007, based on its equivalence to an earlier INRatio device that was approved in 2002. The INRatio2 PT Monitoring System was cleared despite the over 500 malfunction, injury and death reports that had been filed with the FDA in 2007 on the predicate device. In 2010, the INRatio/INRatio2 test strips were cleared, based on substantial equivalence to the devices approved in 2002 and 2007. Once again, the over 2,000 adverse event reports that had been filed on those earlier devices were no barrier to FDA clearance. Finally, in 2012, two new Alere INRatio monitoring systems were cleared, based on substantial equivalence to predicate devices, notwithstanding over 4,000 reports of malfunction, injury and death connected to INRatio devices that had been filed in the previous two years.
“510(k) clearance is not a determination that the cleared device is safe or eﬀective.”
– Institute of Medicine, National Academies of Science, Engineering, Medicine, July 29, 2011
Why the FDA did not act on the thousands of INRatio monitor adverse reaction reports is puzzling. The agency knew of problems with the INRatio monitor as early as 2005. That year, after inspecting the Hemosense (original maker of the INRatio monitor) facility for a period of two weeks, the FDA issued a warning letter to the device maker charging that the company knew its INRatio monitors were generating clinically significant errors with “the potential to cause or contribute to a death or serious injury,” yet had failed to file the required adverse event reports with the FDA. Adverse reaction reports continued to pour in to the FDA as the years passed (over 9,000 by 2014). But they appeared to have provoked little concern.
FDA MAUDE Database Records Adverse Events and Side Effects for Alere INRatio and Other Medical Devices
Adverse event reports on medical devices are held in the FDA’s Manufacturer and User Facility Device Experience, or MAUDE, database. This database was the source of much of the information presented at the workshop.
But manufacturers apparently share a common trait in failing to file required MAUDE reports. At the 2016 workshop, Researcher Kennita Riddick, in the FDA’s OIR office, Division of Immunology and Hematology Devices, said “… all manufacturers do not report as often as they are required.” She also noted that manufacturers may wrongly report an adverse event as a malfunction when it belongs in another category. Ms. Riddick said the FDA is seeing a “trend” in citations issued for “not adequately assessing the effectiveness of their overall quality system” and “failing to adhere to the MDR [medical device reporting] regulation.”
FDA Records Indicate Serious Alere INRatio Safety Issues
The difficulty in protecting consumers is evidently caused in part by non-reporting by the industry. But if all manufacturers of PT monitors are equally lax in reporting, it appears that their devices are not equally dangerous. According to a story in The New York Times, FDA records show a higher number of injury reports associated with the Alere INRatio monitor than other devices on the market. How much higher? The answer to that question is hidden in an FDA slide Ms. Riddick presented showing adverse events associated with all prothrombin time test devices reported to the FDA’s MAUDE database in 2014 and 2015 (see table below).
The slide showed 3,231 reports of malfunction, 384 injury reports and 18 death reports in that two year period. An investigation into those database records revealed something that Ms. Riddick did not mention: 44% of the malfunctions, 90% of the injuries, and 83% of the deaths in that two-year period were linked to one device: the Alere INRatio monitor.
The table below compares the data from Ms. Riddick’s slide to the MAUDE database reports on Alere INRatio safety during the same time period.
*U.S. Food and Drug Administration, Center for Devices and Radiological Health, “Point of Care PT/INR Devices For Monitoring Warfarin Therapy,” Public Workshop slide presentation. Available online at: https://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM491546.pdf. See slide presented by Ms. Riddick on page 202.
** Records available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/search.cfm. Product Class: Test, Time, Prothombin; Event Type: Select from menu; Brand Name: INRatio; Product Code: GJS
Making POC Prothrombin Time Testing Safe
To its credit, the FDA appears to be addressing flaws in the approval process for monitors like the Alere INRatio monitors. Specifically, the agency is considering:
- Requiring external quality controls.
- Testing the devices in a variety of point-of-care settings.
- Implementing measures to improve operator training on the devices.
- Requiring the devices to meet much stricter performance standards.
If enacted, each of these measures will help. As the saying goes, the sooner, the better. Paying close attention to MAUDE database records before a device is cleared for marketing would be a prudent and responsible action. Finally, it is hoped that the FDA will heed the 2011 recommendations of Institute of Medicine experts and reform the approval processes for medical devices so consumers can have confidence that the medical devices they use are safe.
But these reforms will come too late for many. Consumers who have been harmed by the Alere INRatio monitoring system may find out more about their legal options on the Alere INRatio Products Lawsuit page of Baum, Hedlund, Aristei & Goldman.