December 2017—Safety issues related to point-of-care PT/INR testing surfaced in recent years, among them a 2016 voluntary class 1 recall of Alere’s INRatio and INRatio2 monitor systems. “Prior to that, the company that manufactured the device had received thousands of complaints about it,” says Russell Higgins, MD, of the University of Texas Health Science Center at San Antonio.
“What is known is that some patients who may have been kind of ill would get lower INRs, and so theoretically they could be given more warfarin than they should have. They’d be supratherapeutic even though their INR was maybe in the therapeutic range. That was the risk. And it was thought to be related to when the patient was ill and perhaps related to elevated fibrinogen that can [accompany] acute illness. But as far as I know,” Dr. Higgins says, “nobody ever did a study to really show that fibrinogen was the problem.”
A medical device correction issued by Alere on Dec. 5, 2014 cited several contraindications to using the INRatio PT/INR monitor system, including anemia and “any conditions associated with elevated fibrinogen levels.”
The INRatio device was used in the ROCKET AF (atrial fibrillation) trial, Dr. Higgins says, and the trial generated some of the data submitted to the FDA for the clearance of the direct oral anticoagulant rivaroxaban, which can be used in lieu of warfarin (Cohen D. BMJ. 2016;352:i575). Many thought it was possible that the patients in the warfarin arm seemed to have more bleeding because they were receiving more warfarin than they should have based on an INR measured with the INRatio, Dr. Higgins said. “And that made the rivaroxaban appear more safe.” The FDA, manufacturers, and other organizations went back and analyzed the clinical trial data and concluded that rivaroxaban is safe.
Another safety concern: “The FDA had been under fire for some time regarding its 510(k) process for approving medical devices,” Dr. Higgins says (Meier B. NY Times. July 29, 2011). “If you have a new device and you show that it is substantially equivalent to a predicate device, then you can get approval without doing sort of these complicated clinical studies to get it approved.”
These events led to the FDA putting on a public workshop on POC PT/INR devices in March 2016. Dr. Higgins, who was the chair of the CAP Coagulation Resource Committee at the time, presented a session titled, “POC PT/INR: Technical Limitations and Laboratory Accreditation Issues.” The goal of the meeting, according to the FDA, was to identify solutions to address the scientific and regulatory challenges associated with point-of-care PT/INR devices to ensure safety and effectiveness.
Says Corinne Fantz, PhD, of Roche Diagnostics: “We heard from lab experts, clinician experts, FDA experts, etc. Everyone has a unique lens they use to look at this problem the FDA is trying to address, which is to ensure that point-of-care PT/INR instruments are safe and effective.”
“When doing studies as a manufacturer, we want to ensure we have all the right information for the FDA to complete their assessment,” Dr. Fantz says. “Once the FDA suggests a standard, that’s what we work toward, whether it’s in draft or final form.”
Dr. Fantz says the FDA did suggest specific accuracy standards that were “different than the criteria by which current instruments are cleared.
“For example, previous criteria were 90 percent of samples in the INR range from 2.0 to 4.5 needed to match the reference method within 30 percent, and there were no criteria above an INR of 4.5. The new proposal is 95 percent of samples within 20 percent of the reference method and 25 percent above an INR of 4.5.”
In the future, Dr. Higgins predicts, the FDA may be “tightening its criteria for evaluating the substantial equivalence of a new device against an existing device.” In his view, the 510(k) process can be problematic for point-of-care PT/INR devices in that it is assumed that all devices that measure PT/INR are similar. But at least five different types of endpoint determinations are used in the POC devices (Higgins RA, Hemostasis. In: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 5th ed.). “To me, that makes the devices for the INRs different tests,” he says. “Those tests are susceptible to different interferences and limitations because they have different mechanics, different endpoint determinations.”
FDA spokesperson Deborah Kotz informed CAP TODAY in an email that the agency “is continuing to work on guidance on POC PT/INR devices. We are also working on efforts to better educate consumers about how to properly use these devices to monitor warfarin. We cannot comment on the timing of our future actions but this remains a big priority for us,” she wrote.