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FDA to Tighten Standards for Blood-Test Devices

The Food and Drug Administration (FDA) is preparing to tighten standards for devices that test the blood of patients who are on a widely used blood thinner, saying the machines can yield dangerously unreliable readings.

The FDA has received a large number of reports of “malfunctions, serious adverse events, and patient deaths, and this has led the agency to reassess the safety of these devices,” Lea Carrington, an FDA division director, said at an FDA meeting.

The devices are used to measure patients’ clotting rates and adjust the dosing of a blood thinner called warfarin. If the blood is either too thick or too thin, the consequences can be disastrous.

Known as point-of-care devices, the machines are meant to provide immediate results in patients’ homes or doctors’ offices, potentially eliminating the wait for laboratory results and the need to make a special trip for testing. However, reports of problems with point-of-care devices go back more than a decade, and one such device was the subject of a recall in 2014 that warned of potentially fatal errors.

The FDA held an all-day public meeting on the issue last week at which medical experts and industry representatives described the problems, and FDA officials discussed changes the agency is considering.

The FDA announced its plan to hold such a meeting late last year, shortly after the Project On Government Oversight published a report spotlighting problems with devices marketed under the name “INRatio.” Those were the subject of government warnings as early as 2005 and 2006. A 2014 recall notice said affected devices could produce false readings and cause “severe or life-threatening injuries, including death.”

POGO’s reporting raised questions about the soundness of a clinical trial that relied on INRatio devices. The clinical trial—for the blood thinner Xarelto—was co-chaired by Dr. Robert Califf, who was recently confirmed as the head of the FDA.

In a recent report reassessing the Xarelto trial, a European regulatory agency compared device readings used in the trial to measurements performed by a laboratory and found that they often differed. The regulator nonetheless concluded that the risks and benefits of using Xarelto remained unchanged.

The meeting last week underscored that problems go beyond one brand of device and include challenges inherent in using point-of-care kits to measure clotting rates. The devices analyze drops of blood that patients or medical professionals extract from fingertips, and speakers described many factors that can affect the results. Those include the temperature of the patient’s hand, the quality of the patient’s blood circulation, the presence of moisture or contamination, the size of the lancet used, the depth of the finger-prick, the number of blood drops extracted, whether the finger is “milked” for blood, and the amount of time that elapses between the finger-prick and the application of the blood sample to the test strip.

“There’s lots of ways to do a poor fingerstick,” said Rick San George of Alere, manufacturer of the INRatio devices. “There’s lots of ways to apply the sample incorrectly.”

If inaccurate tests lead doctors to prescribe too much blood thinner, patients can suffer bleeding, including strokes caused by bleeding in their brains. If patients are given too little of the anti-coagulant, they can develop clots, which can cause heart attacks, blockages in places such as the lungs, or a different type of stroke.

Accurate readings take on added importance when patients on warfarin start to bleed. An antidote used to stop them from hemorrhaging has different recommended doses depending on a patient’s clotting rate, Dr. Russell Higgins, an associate clinical professor at the University of Texas Health Science Center San Antonio, said at the meeting.

Clotting rates are measured on a scale known as the International Normalized Ratio, or INR. For patients placed on warfarin for an irregular heartbeat known as atrial fibrillation, the desired INR range is typically 2 to 3, meaning that it would take their blood roughly double to triple the normal amount of time to clot.

FDA medical officer Rong Rong illustrated the risks by recounting one report received by the agency.  A point-of-care test performed by a home health nurse yielded a reading of 2.4, which was in the appropriate range. But the patient was suffering from low blood pressure, an increased heart rate, and abnormal bruising. The patient was sent to an emergency room, where the INR was found to be 9.1—indicating that the blood was much too thin. The patient vomited blood in the emergency room and, despite efforts to reverse the blood thinning, bled to death from the gastrointestinal tract, Rong said.

“In keeping with the mission of the FDA, and that is to protect the public health, our goal is to reduce the number of serious adverse events associated with these devices, thereby improving patient safety,” the FDA’s Carrington said at the public meeting.

The FDA pointed to “operator error” as the likely culprit in many erroneous readings.

Randy Fenninger, who gave a patient’s perspective at the FDA meeting, said the devices seem to be easy to use but there was no way for someone like himself to know if the machine was properly calibrated.

“I have kind of crude measures of success . . . .  I thought, ‘Well, I ain’t dead, it must still work,’ ” he said. “Was that confidence misplaced? How would I know?”

Like many other medical devices, point-of-care devices generally make it onto the market without undergoing the level of testing and FDA scrutiny required of pharmaceuticals. A shortcut in federal regulation allows them to win FDA approval if their manufacturers can argue successfully that they are substantially equivalent to devices already on the market.

Dr. Alberto Gutierrez, an FDA division director, said that, without the ability to require clinical trials, the agency is experiencing “angst” in trying to determine the “right thing to do.” He said he hoped the meeting would help the FDA issue new guidance and perhaps new standards.

The meeting’s moderator, FDA scientific reviewer Rachel Goehe, gave a less qualified account of the FDA’s intentions.

“So we propose to obviously tighten” a performance standard to reduce the allowable deviation in readings, Goehe said.

The FDA displayed a slide with the notation “FDA Proposal” laying out in specific percentages a plan to do that.

Laboratory tests have been considered the gold standard in INR measurement, but several speakers at last week’s meeting, including representatives of device manufacturers, said that lab results can also vary widely. Different laboratories employ different methods, they said.

The device problems the FDA is now addressing are far from new.

In a letter to the FDA, Public Citizen’s Health Research Group, a consumer advocate, said that, from the INRatio device’s approval in 2002 through November 2015, there were 9,469 malfunction reports and 1,445 injury reports to the FDA involving INRatio devices.

“There should be premarket testing of all these devices, and the INRatio device should be moved off the market,” Dr. Sidney M. Wolfe, a senior advisor at Public Citizen, said at the FDA meeting.

Alere, maker of the INRatio device, posted a statement on its website saying that the types of issues in INR measurements that could lead to serious adverse events are rare. “Alere will continue to identify factors contributing to such issues, no matter how rare, and take appropriate measures to further mitigate them,” the company said.

Frank LaDuca, an executive at device-maker Accriva Diagnostic, said at the FDA meeting that device-makers share the agency’s interest in accurate testing.

“We don’t take these things lightly, ‘cause it does none of us any good to produce a product that doesn’t work,” LaDuca said. “It does no one any good to produce a product that kills patients.”


Read more articles in the “Drug Problems” series:

By: David S. Hilzenrath
Chief Investigative Reporter, POGO

David Hilzenrath David Hilzenrath is the Chief Investigative Reporter for the Project On Government Oversight.

Topics: Government Accountability, Public Health and Science

Related Content: Food and Drug Administration, Drug Problems, Public Health

Authors: David S. Hilzenrath, Joe Newman

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