Few laboratory instruments are as ubiquitous as the humble blood glucose meter. Yet in recent years, they have become essential not only for managing patients with diabetes, but also for improving outcomes for other groups of patients at the point-of-care. Studies connecting hyperglycemia with poor outcomes have led many hospitals to rely on the convenience of these meters for managing care across a spectrum of hospitalized patients.

Regulators, however, including the Food and Drug Administration (FDA) and the Centers for Medicare and Medicaid Services (CMS), have become increasingly concerned about this practice because none of the meters on the market are FDA-cleared for use in critically ill patients, such as in the emergency department or intensive care unit. In fact, manufacturers submit meters intended for hospital use as over-the-counter devices, which means that FDA clears them based on the same standard as the home-use meters found in drug stores.

In January, FDA issued draft guidance documents that would require manufacturers to meet tough standards before marketing new blood glucose meters. During a March 19 AACC webinar, FDA's Director of the Division of Chemistry and Toxicology Devices, Courtney Lias, PhD, explained the new standards for meters, as well as how FDA will, for the first time, consider them under two categories—professional-use and lay-use. As questions poured in from labs during the webinar, it was clear that many laboratorians feared FDA's guidance for manufacturers would lead to unintended consequences for the lab.

"This guidance document is actually meant to try and help labs, in that right now, manufacturers are basically pushing off the validation onto labs," Lias said. "At the moment, manufacturers are coming to the FDA saying they have an over-the-counter device, when in fact they are trying to sell a device to a hospital, which makes a lot of these uses off-label. If this guidance goes into effect, labs will only have to perform verification, and not validation, for a new meter."

Confusion Over CLIA and FDA Rules

During the AACC webinar, a record number of comments from participants honed in on a common theme: FDA makes rules for manufacturers, but what are labs expected to do in the meantime to meet CLIA standards?

For its part, FDA believes that the draft guidance for professional-use meters could actually make life easier for labs if it were implemented, shifting the burden onto manufacturers to prove that their products really work the way hospitals and labs use them. FDA wants manufacturers to perform rigorous new studies among hospitalized patients and validate new meters according to much tighter standards, instead of "pretending" that their meters are intended for lay users, Lias explained during the webinar (See Box, below).

FDA Pushes for Higher Standards on Blood Glucose Meters

Agency Outlines Separate Tracks for Lay and Professional Use Devices

For the first time FDA is proposing...

The draft guidance for professional-use meters would require manufacturers to demonstrate that 99% of all values are within ±10% of the reference method for glucose concentrations >70 mg/dL. The current FDA standard is 95% of results within ±20%.

This guidance aims higher than the bar set in two existing standards for blood glucose meters. The Clinical and Laboratory Standards Institute (CLSI) POCT12-A3 consensus standard recommends 95% of values within 12.5%. However, this standard is intended for use by clinical labs, not for manufacturers. Similarly, the most recent standard from the International Organization for Standardization, ISO 15197, recommends 95% of values within ±15%. This standard is intended for manufacturers, but specifically for lay-use devices and not hospital instruments.

Abbott, which manufactures blood glucose meters and other point-of-care instruments, said it would like to see FDA conform to the guidelines set by ISO and CLSI. “Adopting and uniformly enforcing these standards would bring immediate and substantial improvements in blood glucose monitoring accuracy to patients and promises the most impact for patient health and safety,” the company said in a statement.

In addition to new performance requirements, the guidance would require more extensive clinical studies of at least 350 patients for a meter intended for the hospital. At least 50 samples each from the surgical and medical intensive care units have to be included.

Separately, a new guidance for meters intended for lay users also bumps up the standard. Manufacturers of new over-the-counter meters would need to demonstrate that 95% of all results fall within ±15% of the reference measurement across the entire claimed measuring range of the device and that 99% of all results are within ±20%. Both guidance documents would also require cleaning and disinfection procedures be validated to avoid transmitting blood-borne pathogens.

FDA has extended the deadline for all comments on the draft guidance to May 7. Comments can be submitted via www.regulations.gov. Search for docket ID FDA-2013-D-1445.

To be sure, FDA and CMS inhabit two different spheres of authority: FDA regulates manufacturers of diagnostic tests and instruments, and CMS enforces CLIA regulations covering clinical laboratories themselves. However, their policies inevitably interact. For example, FDA decides which instruments receive CLIA waiver, which allows almost anyone to perform the test. Currently, all glucose meters are waived automatically because they are submitted to FDA as over-the-counter devices.

Under the draft guidance from FDA, new professional-use blood glucose meters would likely be categorized as moderate-complexity under CLIA and require that manufacturers apply for waived status. According to Lias, FDA designed the clinical studies required under the guidance to speed a manufacturer's waiver application, although the actual standards for waiver remain undecided.

"We know that it is extremely important for healthcare providers to have devices that are CLIA-waived across many settings, both in doctors' offices and in hospitals, where not all of the users would be covered under a high- or moderate-complexity certificate," Lias said. "Even though manufacturers would not automatically get waiver under this guidance, we have designed the document so that a manufacturer could conduct studies that support both waiver and clearance. That way, CLIA waiver could be obtained simultaneously with clearance or very soon after clearance."

But should a new meter not pass muster for waiver and remain in the moderate-complexity category, labs would have to rethink who uses the meter and how to manage a new level of competency assessment, training, and paperwork, noted David Koch, PhD, DABCC, FACB. "This would ramp up the monitoring of the personnel that are using glucose meters, such as nursing aides and patient care technicians. Labs would have to track the meters more closely and restrict who can use them, based on their qualifications under CLIA," he said. Koch is the director of clinical chemistry, toxicology, and point-of-care testing at Grady Memorial Hospital and professor of pathology and laboratory medicine at Emory University in Atlanta.

Moderate-complexity status might also create a dilemma for manufacturers of new meters, according to James Nichols, PhD, DABCC, FACB. "This could place a manufacturer at a market disadvantage and be a disincentive to improve on the current CLIA-waived meters," he said. "The types of studies they are asking for will be expensive trials conducted in hospitals, and they'll have to partner with organizations that have critically ill patients." Nichols is professor of pathology, microbiology, and immunology, associate medical director for clinical operations, and medical director of clinical chemistry at Vanderbilt University School of Medicine in Nashville.

Even if manufacturers are successful in hitting a higher standard for meters, labs will still be on the hook when it comes to implementing them, Nichols added. Changes in the package inserts will likely still require the lab to perform more extensive studies that could be costly and labor-intensive.

This Is Getting Complicated

The separate spheres of FDA and CLIA oversight have also become somewhat blurred on this issue because CMS has recently taken a keen interest in one of the problems FDA's guidance aims to fix—off-label use of waived meters. As a result, the draft guidance is putting a spotlight not only on how FDA might review new devices, but also on how regulators see hospitals' use of existing meters. With a CLIA-waived device, no training is required and usually no external quality control or proficiency testing takes place. However, when used off-label—that is, for any purpose not in the manufacturer's labeling for intended use—the device becomes high-complexity under CLIA, and strict personnel and quality control requirements kick in.

"Any time a laboratory modifies a test system or changes the intended use, which is what is happening now with blood glucose meters that have the critically ill limitation, the test system defaults to high-complexity and the laboratory has to validate the test. But that is actually not a new policy. It's been in place for all modifications since the inception of CLIA," explained Judith Yost, MA, MT(ASCP), director of the CMS Division of Laboratory Services. "But because this specific off-label use is something that has only recently come to light, we certainly are using a light touch on this until laboratories decide how they will respond."

Labs can still use blood glucose meters off-label as long as they validate them, establish performance specifications, and follow personnel and other applicable requirements for high-complexity testing, Yost said. Alternatively, a lab can switch and perform testing in the core lab or use a different type point-of-care instrument. "Laboratories have a number of choices, and if they wish to validate their current meters, we'd certainly give them time to do that," she said.

Adding to the confusion—and worry—among laboratorians, the New York State Department of Health announced in January that the state would enforce all "policies and requirements" related to off-label use of blood glucose meters. In an initial letter to lab directors, the health department included a link to the FDA draft guidance, apparently connecting FDA's action to what many laboratorians felt amounted to a change in policy for New York labs.

In a second letter, the state clarified that labs should not try to perform the validation studies described in the FDA draft guidance, but rather use a standard developed by the Clinical and Laboratory Standard Institute (CLSI), "Point-of-Care Blood Glucose Testing in Acute and Chronic Care Facilities," or POCT12-A3 for short.

In fact, during the webinar, Lias specifically asked labs not to attempt to use the FDA guidance themselves, and referred labs to the CLSI document for developing their own policies and procedures around blood glucose meters. "I can't emphasize enough that these guidance documents are not meant for laboratories or hospitals. They are meant to describe studies that manufacturers should do to submit devices for clearance," she said.

Aside from CMS, accrediting organizations seem to be taking a wait-and-see approach. The Joint Commission is holding off on changing standards or surveys until the FDA guidance is finalized. Labs in New York, however, are expected to follow state law and regulation, noted John Gibson MA, MT(ASCP), DLM, associate director of the Joint Commission standards interpretation group.

The College of American Pathologists (CAP) has not indicated any changes either. "The CAP laboratory accreditation program has a checklist requirement that requires laboratories to follow manufacturer instructions or have documentation of appropriate validation studies if the laboratory has modified the test," wrote Bruce Williams, MD, FCAP, chair of CAP's council on scientific affairs, in a statement to CLN.

Is There Really a Problem?

Both Koch and Nichols emphasized that better technology for blood glucose meters is welcomed by labs, as is FDA's decision to separate the requirements for home-use versus professional-use instruments. They also agreed, however, that FDA took a step too far in the requirements for professional-use instruments, and questioned whether such high standards that go beyond the CLSI consensus would actually improve patient care.

While no instrument is perfect, Koch noted that with proper oversight from the lab, blood glucose meters already on the market have proven successful in glycemic control protocols. "Hospital laboratorians and endocrinologists who are working with surgeons and others in the intensive care units know that this close monitoring is beneficial, both in decreasing length-of-stay and improving outcomes for patients," Koch said. "We monitor the meter, we monitor the people who are using them, and we've been pleased with the performance."

Most laboratorians are well aware of the limitations of these meters, and have implemented point-of-care testing programs in which meters are validated on hospitalized patients as part of the routine implementation of new devices, Nichols noted. "I think the question really is, will improving glucose meter performance actually improve patient outcomes? I'm not certain that the standards FDA has proposed actually relate to studies that show improved outcomes for patients that are on intensive insulin management," Nichols said. "We need to focus on what is sufficient for that medical use."

However, one positive development in the draft guidance is new provisions for infection control, Nichols emphasized. These include new recommendations for cleaning, as well as manufacturing standards that would make meters more durable and resistant to repeated disinfection cycles. "Those are really good requirements that I think will improve patient safety," he said.

The Human Factor

FDA's push for higher standards for blood glucose meters will mean that new instruments will be more accurate. But experts also cautioned that even if manufacturers perform the robust clinical studies laid out in FDA's draft guidance, patient care would not automatically improve. It would still be up to labs to ensure complete quality control that takes human error into account.

"Manufacturers can provide the best technology out there, but it all comes down to the operators and how they use the device," Nichols said. "From patient preparation to finger stick technique and applying the sample, all of these factors come together in terms of the final result. Even with a meter that achieves the 10% total error FDA is proposing, operator variability could nullify all the improvements the manufacturer makes."

According to Koch, these same human factors also make a CLIA complexity designation less relevant in actual use. "Education doesn't necessarily equal proficiency with blood glucose meters," Koch said. "A phlebotomist who is really focused can do a great job with only a high school degree—it's about the person and his or her performance that matters."

When errors do occur with blood glucose meters, usually a pre-analytical issue is to blame, Koch said. "It's more than meters and test strips. If the meter doesn't work, it's often that the sample wasn't acquired properly, or the patient is in shock and their capillary circulation isn't adequately in agreement with plasma. For the most part, the performance of the meters themselves is good."