May 2010: Volume 36, Number 5
Blood Glucose Meters
Is FDA Ready to Tighten Up Accuracy Standards?
By Bill Malone
After a decade of squabbling over how accurate blood glucose meters (BGM) need to be and how they should be used in hospitals, manufacturers, the Food and Drug Administration (FDA), and other stakeholders now appear to be coalescing around the concept of a two-track regulatory approach to finally distinguish the needs of lay users monitoring diabetes at home versus healthcare professionals maintaining tight glycemic control (TGC) protocols in clinical settings. How this plan will be fleshed out depends on how FDA digests input from its recent public meeting, and comments submitted by stakeholders, as well as on forthcoming guidance on the subject by professional societies. For now, the consensus from stakeholders is that the overall accuracy of BGMs should be at least ±15% total error at the upper range of glucose results, tighter than the current ±20% standard codified in the 8-year-old ISO standard used today by FDA to clear BGMs for market.
Nearly 400 stakeholders convened for the meeting held March 16–17, in Gaithersburg, Md. and organized by FDA’s Courtney Harper, PhD, director of the division of chemistry and toxicology devices in the center for devices and radiological health. “Moving forward, we know that there is a need out there for convenient point-of-care meters in the hospital setting, and that there are technologies that are already good enough for that or very close,” said Harper. “We are in a unique position of potentially being able to give more guidance and clarity on how these devices need to be evaluated. We want to find a way to address this so that it’s a win-win, so doctors have access to the devices that can accomplish what they need.”
The controversy over BGM accuracy comes on the heels of an intense debate in the medical community about the benefits and safety of tight glycemic control (TGC) in hospitals. Stakeholders have argued that recent studies such as Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR; NEJM 2009;360:1283–1297), which cast doubt on TGC, were flawed due to use of imprecise BGMs. In fact, the original studies that first demonstrated the value of TGC in intensive care settings used very accurate arterial blood gas instruments. Now, some defenders of TGC have become critics of BGMs, lamenting their common use in TGC protocols. This has drawn renewed scrutiny from regulators, clinicians, and laboratorians on the meters themselves, unique devices that receive special FDA clearance simultaneously for over-the-counter (OTC) and professional use.
The Controversy on Accuracy
Few, if anyone, would dispute that the landmark 1993 Diabetes Control and Complications trial (DCCT) clearly showed the benefit of monitoring diabetes with BGMs (NEJM 1993;329:977–986). Individuals who monitored their blood glucose regularly experienced delayed onset and slower progression of clinically important retinopathy, including vision-threatening lesions, nephropathy, and neuropathy, by at least 35% and as high as 70%.
However, the importance and utility of BGMs doesn’t necessarily mean all the benefits of their use are owed to their accuracy, emphasized William Clarke, MD, chief of the division of pediatric diabetes and endocrinology at the University of Virginia School of Medicine in Charlottesville, Va. Glycemic variability, when blood glucose levels bounce up and down throughout the day, has been shown to damage blood vessels, and Clarke believes it’s this variability that’s a main culprit in diabetes-related complications, even when the mean of these dips and peaks equals out to an acceptable average measured via hemoglobin A1c (HbA1c).
“Clearly even very old meters were useful enough for DCCT,” he said. “But I think that what really was shown there was that intensive care improved outcomes, not necessarily HbA1c. So much literature suggests that glucose variability may be as important as average blood glucose. And if in fact you have a meter that’s not very accurate, but it’s so easy to use that you’ll use it over and over again and you’ll make more decisions, then your glycemic variability will improve, even though you’re average blood glucose is off.”
Clarke noted that the current 20% total error rate for BGMs is only for 95% of the results, and the outliers in the other 5% could adversely affect some people using BGMs to monitor diabetes. “If you have enough total numbers then those outliers don’t seem like much on paper, but if you’re a patient trying to make an important decision, you might be in real trouble,” he said. “There are patients who, using an insulin infusion pump, can give smaller and more accurate doses of insulin that require an accurate reading from the meter. Shouldn’t these patients benefit from all the hard work they’re doing managing their disease?”
Manufacturers Juggle Demands
BGM manufacturers are quick to point out that, because BGMs are both a tool for healthcare professionals and a consumer product, manufacturers must take a wide angle view to meet lay users’ demands for usability, in addition to analytical performance of the meters. “AdvaMed member companies share the goal of enhancing meter accuracy standards, and support updates to ISO 15197,” said Steven J. Brotman, MD, JD, senior vice president for payment and healthcare delivery policy for the Advanced Medical Technology Association (AdvaMed) in a statement. “Specifically, we support a tightened accuracy standard in Section 7 of ISO 15197 for self-monitoring/home use meters from the current standard of ±20% to ±15%, a 25% improvement over the current minimum accuracy.”
During the FDA meeting, Brotman and other manufacturer representatives enumerated the many improvements in BGMs that manufacturers believe contribute to usability and ultimately, better outcomes for patients. “For more than 30 years, the medical technology industry has been committed to designing and manufacturing home blood glucose meters that meet the needs of people with diabetes and lead to better healthcare outcomes,” noted Brotman. “These advancements in glucose monitoring are responsible for advancing patient care and preventing and reducing harmful, costly complications.”
Brotman highlighted the fact that manufacturers also fully support efforts to develop increased accuracy requirements for BGMs used in hospitals and long-term facilities, since the current ISO standard is specific to self-monitoring/home use—not to professional use—even though FDA review of BGMs means clearance for both.
Also presenting at the FDA public meeting, Mike Flis, regulatory affairs principal for Roche Centralized Diagnostics, emphasized that BGM technology is limited by many factors other than achievements of accuracy, such as using whole blood with potential interference from endogenous and exogenous substances, environmental variability, misuse outside of the manufacturer’s control, and constraints of cost and test convenience (See Box, below). “Industry is working to co-optimize across these spaces and determine the best tradeoffs to deliver maximum medical benefit and patient value,” he said. Manufacturers would also support further harmonization of study design and labeling to make comparing label claims easier and provide increased transparency to users.
Lab Instruments versus Point-of-care Meters
At the recent FDA public meeting on blood glucose meters, March 16–17 in Gaithersburg, Md., manufacturers drew attention to the many ways in which blood glucose meters, as consumer products, differ from lab methods for measuring glucose. Manufacturers highlighted the fact that they must balance accuracy with many other factors to make sure meters work in the hands of lay users. Here’s a look at how the two compare.
|Standard reference materials
||No standard reference materials|
|Elimination of hematocrit effect by analysis of serum or plasma
||Hematocrit effect mitigated by measurement or algorithms|
|Can cost more than $10,000
||Costs less than $100|
|Maintenance is more than $1,000 a year
||No maintenance required|
|Calibrated many times daily
||No user calibration|
||Variable temperature, altitude, and other factors|
|Controls run frequently
||Control solution use limited|
|Large, stationary, sensitive to shock
||Small, portable, resistant to shock|
|≥5 mL sample
||≤1 µL sample|
|≥60 second throughput
||≤10 second throughput|
|±4% to ±10% inaccuracy
||Inaccuracy is generally ≥2X reference method (laboratory instrument)|
Since many clinicians would be satisfied if patients would stick with a solid program to manage their illness and use a meter regularly, stakeholders at the FDA public meeting for the most part noted that the most distressing problem involving BGMs is their use in hospitals for TGC. “Most of us agree that the accuracy issue is more important in the inpatient setting versus the outpatient setting, yet a lot of what is discussed is focused on the outpatient setting,” said Irl Hirsch, MD, professor of medicine in the division of metabolism, endocrinology and nutrition at the University of Washington School of Medicine, Seattle. Hirsch served as the moderator of the TGC discussion at the FDA meeting. “We really haven’t done a good job of separating the two issues. I think most people would say that in outpatient settings we are doing okay, especially compared to 15 to 20 years ago.”
Despite the fact that some institutions have been successful with TGC using BGMs, most hospitals are not sufficiently vigilant to take enough blood glucose measurements to overcome a meter’s analytical limitations, explained Hirsch. “The more testing you have, the less critical any individual data point is if the meter’s accuracy is not as good as it should be,” he said. “The reality, however, is that most places do not have a culture of tight glycemic control, and they don’t do enough careful testing to make TGC safe.”
The Regulatory Puzzle
According to their labeling, BGMs are indicated for use by lay users at home or by healthcare professionals in clinical settings for ongoing management of individuals with diabetes. There is currently no distinction between performance requirements for over the counter (OTC) and professional use. According to some stakeholders, this is where there will be an opportunity for FDA to draw a line between OTC-style meters and those just for hospitals, especially when it comes to TGC.
Before a manufacturer can market a BGM, FDA requires that 95% of individual results fall within ±20% at glucose concentrations of ≥75 mg/dL and 95% of individual glucose results fall within ±15 mg/dL of the reference measurement at glucose concentrations of <75 mg/dL. These minimum accuracy requirements come directly from an ISO document currently under review (See Box, below). The revision of this standard is where FDA and manufacturers seem to agree that it makes sense to tighten accuracy to ±15% for the upper level of glucose readings.
Forthcoming Standards Documents Will Shape Regulation
Two forthcoming documents dealing with blood glucose meters will offer more definitive guidance on how FDA might proceed in the quest to satisfy needs of both lay users and healthcare professionals.
ISO 15197: In vitro diagnostic test systems—Requirements for blood glucose monitoring systems for self-testing in managing diabetes mellitus. From the International Organization for Standardization (ISO) and still in the “preparatory” stage, this document specifically addresses the needs of lay users.
Available on the ISO website.
POCT12-A3: Point-of-Care Blood Glucose Testing in Acute and Chronic Care Facilities; Approved Guideline—Third Edition (Formerly C30-A2). From the Clinical and Laboratory Standards Institute (CLSI), with a projected completion date of June 2011, this guidance is aimed at healthcare professionals.
Available on the CLSI website.
“FDA is very plugged in to the ISO process,” said Harper. “I think that we are moving in parallel to some degree, and as much as we can coordinate with the outcome of the ISO documents, that’s certainly something we’d be interested in. But we need to move forward as quickly as we can to make sure that if there are changes we need to make to devices in the U.S. that we make them, and if that can happen faster than the ISO process, then it may do so. But regardless of how fast that process moves, there are still some issues FDA would need to address on its own.”
The fact is, many BGMs could probably meet this higher standard already, according to the agency’s own data. A recent FDA evaluation of glucose meters cleared over the past 2 years and discussed during the public meeting found that approximately 50% would meet ±15% at ≥75 mg/dL and approximately 72% would meet ±10 mg/dL at <75 mg/dL. These findings agreed with comments by several speakers at the meeting who noted that their own data indicated that BGM performance has been increasing, even though the FDA standard has remained the same for the past 8 years.
Beyond the changes to the ISO standard that FDA currently uses, the larger issue that has AACC and other stakeholders advocating for a two-track solution is the fact that FDA grants CLIA waivers automatically for BGMs intended for OTC use. With a CLIA waiver, no training is required and no external quality control or proficiency testing takes place, noted Carol Benson, during the FDA meeting. Benson is associate director in the division of chemistry and toxicology devices in the Office of In Vitro Diagnostics and Device Evaluation and Safety.
If the current automatic waiver for all OTC BGMs—even those used in professional settings—was dropped, manufacturers would have to submit waiver studies and meet stricter requirements. Normally, a CLIA waiver would require that 95% of results fall within ±15% for values ≥75 mg/dL and ±12 mg/dL for values <75 mg/dL. Additionally, the other 5% of the values not ‘counted’ would be reviewed to make sure there weren’t too many distant outliers, Benson explained. Typically, waived devices require much more robust user studies as well. A minimum 360 samples must be tested versus 100 for non-waived devices, testing must take place at a minimum of three different sites versus one, and over a 2-week time period instead of at a single point in time.
Although Congress revised CLIA provisions in 1997 to make it clear that any test—including BGMs—cleared for home use also automatically qualify for CLIA waiver, professional use versions do not have to be automatically waived in all cases. This loophole gives FDA enough room to consider higher standards for professional use BGMs without a change in the law.
Harper emphasized that any such change would not come suddenly or without warning to manufacturers. “If we were to make major changes to how meters were cleared that would be significant for manufacturers, doctors, or patients, we will make sure it is done in a transparent manner that allows for public discussion so that we could receive comments before any major changes were implemented,” she said. “The timeline for that kind of change is unpredictable. We’re going to be moving as fast as we can to move that discussion. In terms of priority, it is a high priority, and we’ll be moving on it relatively quickly, but in terms of a timeline, I could not predict that right now.”
The Lab’s Expertise
Even as FDA and manufacturers work on clarifying regulation and improving meter accuracy, hospitals will depend on the expertise of laboratorians as physicians try to make sense of conflicting evidence on TGC and less-than-ideal accuracy from BGMs, according to Hirsch. “The bottom line is that the FDA is going to have to make some tough decisions about meters and what the new standards should be for accuracy,” he said. “But what FDA can’t do is dictate how many resources and how much attention hospitals put into this area. The reality is that many hospitals struggle with TGC and don’t make it enough of a priority.”
Hirsch emphasized that only because of a long-standing culture of close attention to TGC has his institution been successful with the program using BGMs. Essentially, nurses test frequently enough to make up for any errors in measurement. “The key is measuring frequently, because if accuracy is off for one reason or another, you have enough numbers that you can usually ease the error with more measurements,” he said. “Having said that, even though we’ve done fine, I think it’s safe to say that most hospitals could not do what we do.”
Hospitals especially need laboratorians to help with staff education, stressed Clarke. “This is a matter of training the people who are going to be doing the testing, helping to minimize errors by making sure that the patient’s fingertip is warm, making sure it’s clean, that there is no more alcohol on it, that the QC has been done and that the results are written down correctly,” he said. “Ideally I’d like to see a device developed for use in the ICU, but I’m not sure there is going to be that much of a market for that because of cost.”
In addition to training, laboratorians have an important role in managing BGM protocols and data. “I think the main thing laboratorians can do, since they can’t change the technology, is to help us use the technology that we have to get the glucose information from the bedside to all the physicians as quickly as possible,” Hirsch said. “With electronic medical records, as soon as the nurse checks the glucose level, ideally in the room, the data should go into the patient’s electronic medical record so a physician on a different floor or even in a different office miles away from the hospital can see the glucose, see the insulin, and that information can get to the right people right away.”
Often, the system in most hospitals consists of a nurse writing down glucose results on a piece of paper that goes into his or her pocket, which, only later, is transferred to the patient’s paper chart, Hirsch explained. “There isn’t a good system for tracking the blood sugars in real time, and often you can’t see what’s going on with the insulin and the glucose levels until the day after everything has happened. How much time have we all spent over the years just hunting for the piece of paper or the log book that the insulin doses and the glucose levels are on? That to me is the problem. And this is because many hospitals don’t have the infrastructure to use some of these electronic solutions.”