The FDA final guidances for point-of-care (POC) and home-use glucose monitors might not have given industry everything it wanted compared to the draft guidances, but the agency said in a webinar that the accuracy goals for POC systems will be substantially eased from what some saw as unattainable accuracy benchmarks.
The agency published both final guidances in October after hearing from industry that the draft guidances flew against some recognized standards, including an ISO standard for glucose meter reading ranges. Another subject of some concern was the CLIA status of POC test units, but the lag time of more than two and a half years between the draft and final guidances was perhaps the best indicator of the difficulty the FDA had in reconciling the features of the draft with the criticisms the agency received. (See Medical Device Daily, Oct. 10, 2016.)
The FDA's Leslie Landree, team leader at the agency's diabetes diagnostics office, said during a November webinar that the POC draft had proposed to require that 99 percent of meter results be within 10 percent of the comparator method for glucose readings that exceeded 70 milligrams per deciliter (mg/dL). That metric is now 95 percent of results coming within 12 percent of the comparator results, although the threshold for glucose concentrations was raised to those exceeding 75 mg/dL.
The POC draft's standard for glucose concentrations falling below 70 mg/dl was set at 99 percent of readings within seven mg/dL of the comparator standard, but the draft also required that all values be within 20 percent of the comparator. The FDA change to this set of metrics – again, using the revised threshold of concentrations at or below 75 rather than 70 mg/dL as was seen in the draft – to within 12 mg/dL for 95 percent of readings, while 98 percent of all readings would have to fall within either 15 percent or 15 mg/dL of the comparator standard.
Landree, who said at the outset that the requirements for POC and home-use monitors exhibit considerable overlap, remarked that POC regulatory filings "should also include an evaluation of the effect of potentially interfering exogenous substances," including acetaminophen, which is known to interfere with glucose meter readings despite that the drug has no apparent effect on glucose levels. Premarket filings for POC systems will have to include risk analyses for drugs that are commonly used in the intended use population, Landree said.
Approvals and clearances of POC glucose monitors as reviewed under the terms of the guidance will not automatically be CLIA-waived, Landree said, but she added that studies of such devices as described in the guidance should facilitate those waivers. She stated further that the accuracy user study requirements are particularly pertinent for supporting CLIA waivers, pointing to features such as the number of samples used in a premarket study as particularly useful in this context. The guidance further offers instruction on development of a dual 510(k)/CLIA submission, she noted.
Landree said the requirement that a study of a POC system include 350 patient samples per claimed sample type or matrix source is a larger set of samples than the agency routinely sees in applications, but she said that samples from different locations, such as arterial, venous and capillary sources, can be obtained from each patient, thus constraining the minimum volume of enrollment in a study. Addressing the requirement that a study include samples that span the range of glucose concentrations, Landree said samples can be spiked or subjected to glycolysis to achieve the concentrations necessary to fulfill this mandate should the original set of samples fail to cover the required range.
ACCURACY FOR HOME-USE DEVICES UNCHANGED
On the point of home-use devices, Landree said that 510(k) filings for over-the-counter home use "allows for automatic CLIA waiver categorization," but she said studies of OTC devices must exclude any specific instructions on device use beyond those found in product labels. At least 10 percent of enrollees must have had no prior experience with home-use monitors as well, and glucose test strips used in these studies will have to have undergone the type of shipping and handling routinely encountered in ordinary patient usage.
Studies of devices for OTC home use can also make use of sample spiking or glycolysis in order to provide the needed range of glucose measurements, but Landree noted that the thresholds for accuracy in the final home use guidance remain the same as seen in the draft. For these devices, 95 percent of results in the accuracy study must be within 15 percent of the comparator method "across the entire claimed measuring range," Landree stated, adding that 99 percent of the results have to be within 20 percent of the comparator method's results.
Landree said the agency heard from stakeholders that an OTC home use unit might not reliably pick up very low concentrations of glucose, and that physicians have advised the agency that lay users may find a narrowing of the range of results acceptable. However, she said the range of results seen in an accuracy study should be no more narrow than 50-400 mg/dL.
The requirements for interfering agents is the same in the two final guidances, Landree said, remarking that infection control requirements are "very similar" in the two final guidances as well. There is a difference in the two documents' handling of how a sponsor must assess the effect of hematocrit levels on device performance.
The home-use guidance cites a hematocrit range of 20 percent to 60 percent as the ideal set point, but Landree said the agency will go along with a range as narrow as 30-55 percent. In contrast, the POC guidance cites a range of 10-65 percent as the target validated figure, although any device intended to be used by patients with a broad range of oxygen levels should be evaluated so as to demonstrate device usability for these patients.