DRAFT

July 14, 2016

Center for Devices and Radiological Health

Food and Drug Administration


Bldg. 66, Room 1116

10903 New Hampshire Ave.

Silver Spring, MD 20993

 

RE:    Docket No. FDA-2016-N-0001

July 21 Meeting of the Clinical Chemistry and Clinical Toxicology Devices Panel of the Medical Devices Advisory Committee

The diaTribe Foundation and members of the diabetes community signed below are pleased to submit comments to the Food and Drug Administration (“FDA” or “Agency”) regarding the July 21 meeting to discuss a change in intended use of Dexcom’s G5 Mobile CGM.

We support the application to enable patients to use the Dexcom G5 device as a replacement for their blood glucose meters (BGM) and to make treatment decisions based on the interstitial fluid glucose concentration reported by the CGM.

Neither BGMs nor CGMs are perfect devices, but we ask the FDA to consider: (i) the existing risks and dangers of use BGMs alone for making treatment decisions; and (ii) the additional safety layers CGM adds to diabetes decision making.

As the FDA weighs all the risks and benefits of approving this PMA supplement, we hope the following comments will be considered.

Comment Summary

1. Many currently available blood glucose meters used for insulin dosing fail to meet ISO and FDA accuracy criteria, and may be less accurate than Dexcom’s G5.
2. Many patients and healthcare providers feel that CGM is safer than BGM with the addition of real-time data (288 readings per day), alarms, trend arrows, and remote monitoring. CGM adds redundancy for making safer diabetes decisions.
3. Many current CGM users already use the information to make treatment decisions; however, proper patient and healthcare provider education cannot occur without this label update.
4. CGM can minimize the risk of a false high caused by dirty hands, a concern for safe dosing of insulin.
5. A replacement claim for CGM is needed before Medicare will even consider coverage, and these are the patients most in dire need of CGM.
6. Dexcom’s G5 already has BGM replacement label claims in Europe. We urge the FDA to reach out to its European counterparts to learn from this experience.
7. Blood glucose meters are not currently FDA approved for dosing insulin or making treatment decisions, and some were cleared over 10 years ago under more lenient accuracy criteria. Why are CGM devices held to a higher standard?
8. A replacement claim could expand the number of patients willing to go on CGM and the number of providers willing to prescribe it.
9. Insulin is a highly dangerous drug, and equipping a wider spectrum of patients with more comprehensive real-time data and alarms could prevent hospitalizations.
10. Diabetes is a highly burdensome, 24/7 disease, and the quality of life benefits from fewer fingersticks should also be factored into the FDA’s decision.

Detailed Comments

1. Many currently available blood glucose meters (BGM) used for insulin dosing fail to meet ISO and FDA accuracy criteria, and may be less accurate than Dexcom’s G5 (MARD: 9.0% vs. YSI). We urge the FDA not to view fingerstick meters as perfectly safe devices; they too have inaccuracy, and often, that inaccuracy exceeds CGM. As patients are increasingly forced to use lower quality, offshore glucose monitors, the real-world accuracy of fingersticks can present a substantial risk for safe insulin dosing. A highly respected key opinion leader in diabetes recently characterized some offshore blood glucose monitors as “so inaccurate that “a dartboard would do better.” Just a few examples from the literature:

• A 2012 study (Freckmann et al., J Diabetes Sci Technol) found that among 34 BGM systems assessed, only 53% (18) met the then-draft revision of ISO 15197 (≥95% of the results within ±15 mg/dl (<100 mg/dl) or ±15% (≥100 mg/dl) of reference).
• A 2013 study (Brazg et al., J Diabetes Sci Technol) tested seven commonly used BGMs, with an alarming six of the seven failing to meet accuracy standards according to then-draft revision of ISO 15197.
• Some meters, such as Prodigy’s Autocode, are disturbingly unsafe for dosing insulin. A 2012 study (Prohaska et al., J Pharm Pract) concluded that the system was “inaccurate,” with 25% of readings falling outside ±20% of reference. The Prodigy Autocode system made up a striking 27% of Medicare claims for mail order test strips in late 2013 (Parkin & Davidson, American Journal of Managed Care 2016).

2. Many patients and healthcare providers feel that CGM is safer than BGM with the addition of real-time data (288 readings per day), alarms, trend arrows, and remote monitoring. CGM adds redundancy for making safer diabetes decisions. We believe CGM can reduce the risk of an insulin overdose relative to fingersticks alone, as it is less reliant on individual point-in-time blood glucose values for making decisions. Consider the following examples:

1. A patient uses fingersticks alone for making treatment decisions, taking five fingersticks per day.
2. A patient wears CGM and calibrates it twice per day with fingersticks (usually when waking up and in the evening), using the system for making treatment decisions at all other times. The patient receives a glucose reading every five minutes, plus alarms and trend arrows.

Which patient is safer? Which patient has more redundancy in the system for safely making decisions? Patient A has far less information to make an informed diabetes treatment choice, and thus, higher risks for negative outcomes (e.g., an accidental insulin overdose).

CGM adds a 30-40-fold increase in data density (288 readings per day vs. 4-10 fingersticks), plus alarms and trend arrows to bring more safety to diabetes decision making. In the pivotal study of Dexcom’s Software 505 (used in G5), the system accurately detected hypoglycemia 91% of the time in adults at the alert threshold of 70 mg/dl; hyperglycemia was accurately detected 99% of the time at the common threshold of 180 mg/dl.

BGM cannot approach such hypoglycemia and hyperglycemia detection accuracy – four to six fingersticks per day simply isn’t enough data to keep patients safe.

3. Many current CGM users already use the information to make treatment decisions; however, proper patient and healthcare provider education cannot occur without this label update. This change in intended use is a formality for those already using CGM to make treatment decisions, but it will allow Dexcom to keep these patients safer – officially educating them on best practices for dosing insulin based on CGM readings, adding appropriate warnings and training to the G5 app and educational materials, etc. If this label update is not approved, patients will continue dosing insulin off their CGMs anyways, but without the benefits from proper education, guidance from healthcare providers, and any warnings to mitigate potential risks.

4. CGM can also minimize the risk of a false high caused by dirty hands, a concern for safe dosing of insulin. A situation that threatens patient safety with glucose monitoring is a false high – e.g., a measured glucose reading of 300 mg/dl when the blood glucose is actually 80 mg/dl. Taking insulin in such a case could lead to severe hypoglycemia. False highs typically stem from unclean hands: for a glucose meter that needs a 0.3 microliter blood sample, a speck of glucose on the finger – no more than the weight of a dust particle -- will increase the reading by 300 mg/dl (Ginsberg, Journal of Diabetes Science and Technology 2009).

Patients routinely do not wash their hands before taking fingersticks, which can elevate the risk of a false high. This presents a problem for both BGM and CGM devices, but the risk with BGM alone is far greater.

With fingersticks alone, patients must rely on each individual glucose measurement for making a treatment decision – there is no safety net. With CGM, the history of fingerstick calibrations since the sensor startup is taken into account, reducing the reliance on any one fingerstick, and thus, limiting the chance that a single test with a dirty finger will falsely elevate a reading used for dosing insulin.

Product labeling, on-device/on-app alerts, and proper education with this label update can encourage hand washing before fingerstick calibrating Dexcom’s G5 CGM, mitigating the risk of inaccurate device calibration. Time of day also plays a role in safe calibration with CGM: many patients choose to perform CGM calibration in the morning and evening – convenient times when they are more likely to be at home and to wash their hands.

Last, CGM can actually serve as a confirmation that fingersticks are accurate; not the other way around. For instance, upon seeing a fingerstick value of 280 mg/dl, a CGM user will double-check the value, and in many cases, note a measured interstitial fluid glucose that is much lower (e.g., 80 mg/dl). This discrepancy is a red flag with a system as accurate as Dexcom’s G5, and often prompts users to wash their hands and retest. Much of the time, it’s the meter that is reading falsely high (from dirty hands), and the CGM can actually prevent a dangerous overdose of insulin. In that scenario, CGM can be safer than a fingerstick meter.

5. A replacement claim for CGM is needed before Medicare will even consider coverage, and these are the patients most in dire need of CGM. The T1D Exchange clinic registry reported a remarkably high frequency of severe hypoglycemia in older adults with long-standing type 1 diabetes, resulting in seizure or loss of consciousness: one or more such events during the prior year was reported by 1 in 5 participants ≥65 years of age with ≥40 years’ duration of diabetes (Weinstock et al., J Clin Endocrinol Metab 2013). CGM offers potentially lifesaving safeguards for these patients, including hypoglycemia alarms, trend arrows, and detection of overnight lows – none of which are possible with fingersticks alone. CGM needs a label replacement claim before it can qualify for a Medicare benefit category. Until that happens, Medicare will not even consider covering it.

As the FDA considers this PMA submission, we hope it keeps the Medicare population in mind and recognizes the many benefits of potentially bringing CGM to those most at risk of life threatening lows.

6. Dexcom’s G5 already has a replacement claim in Europe. We urge the FDA to reach out to its European counterparts to learn from this experience. How can real-world data from thousands of patients dosing insulin off their sensor readings inform the FDA’s perception of the actual risks and benefits? 

7. Blood glucose meters are not currently FDA approved for dosing insulin or making treatment decisions, and some were cleared over 10 years ago under more lenient accuracy criteria. Why are CGM devices held to a higher standard? The intended use of current fingerstick meters generally reads along the lines of: “as an aid in monitoring the effectiveness of a diabetes control program.” We are not sure why CGMs must now prove they are safe for dosing insulin, when fingerstick meters are not held to the same standard – many of which were cleared more than a decade ago under a lower accuracy bar.

8. A replacement claim could expand the number of patients willing to go on CGM and the number of providers willing to prescribe it. CGM has proven its ability to reduce dangerous hypoglycemia and hyperglycemia, but for many considering the technology, the need for confirmatory fingersticks presents a barrier to trying it. We believe this label claim could expand the number of patients willing to try CGM, and the number of providers willing to prescribe it. That would bring benefits to public health, something we encourage the FDA to weigh in this decision.

9. Insulin is a highly dangerous drug, and equipping a wider spectrum of patients with more comprehensive real-time data and alarms could prevent hospitalizations. Insulin-related hypoglycemia and errors cause over 97,000 Emergency Department visits each year in the US (Geller et al., JAMA Intern Med 2014). How many of these stem from fingerstick meters, and how many could be avoided if all insulin-using patients had access to CGM?

10. Diabetes is a highly burdensome, 24/7 disease, and the quality of life benefits from fewer fingersticks should also be factored into this decision. Fingersticks are time-consuming and highly visible, and the current adjunctive label for CGM adds more burden to patients – not just wearing a CGM device, but taking fingersticks before making any treatment decisions. A replacement claim will bring quality of life benefits to patients, who will not need to take as many additional fingersticks. We ask that the FDA take that advantage into account when weighing this decision.    With this meeting, the FDA has a historic opportunity to protect patient safety, promote public health, enhance patients’ quality of life, and promote next-generation product innovation.

Thank you so much for the opportunity to comment and bring patient perspective to this important meeting.

Sincerely,

Kelly Close, Adam Brown, Ava Runge and members of the diabetes community (sign the letter here!)