November 6-8, 2014; Bethesda, MD – Days #2-3 Highlights – Draft

Executive Highlights

The 14th Annual Diabetes Technology Meeting wrapped up over the weekend following two days of packed discussion on controversies in artificial pancreas development, postmarketing BGM surveillance, the latest in CGM, the role of mHealth, and other hot diabetes tech topics. We salute DTS for having this gathering; it is incredibly important to assist developers of technology to understand what features and levels of performance will be needed, and what is likely to work and not work. This convening continues to help make that happen. It is also extremely important for the field to see new types of technologies presented for consideration for developers to incorporate into their products, and, of course, for networking between scientists, clinicians, FDA, large companies, small and medium-sized companies, and patients and patient advocates (who are part of all the previous groups as well – those very active in social media are also included). Over the years, we have seen more and more FDA regulators attend this event (we heard/saw Drs. Courtney Lias, Stayce Beck, Patricia Beaston, and Ms. Arleen Pinkos) so they can learn what is being developed and interact with the scientists and engineers in an informal setting. In the future, we hope to see more payers coming as well and believe the quality of the conversation certainly merits this. Below, we have enclosed our Top 10 Highlights from days #2-3 followed by more detailed coverage of the most notable presentations and panel discussions.

1. A star-studded panel discussion on the Performance of Cleared Blood Glucose Monitors featured the most enthusiasm we have heard to date from the FDA on the DTS Surveillance Program and insight into the FDA’s ability to mandate device meet a certain level of accuracy – it’s possible, but it would take five to seven years to get this into place. We continue to express concern about who will cover the costs, but it’s certainly clear that surveillance is needed and we love the idea that eventually enough resources would exist that this could be taken on and paid for solely by FDA.

2. A provocative session entitled, “Controversies in Developing the Artificial Pancreas,” did not disappoint, with expanded multicenter study data from Dr. Ed Damiano (Boston University, MA), a single vs. dual-hormone comparison by Dr. Roman Hovorka (University of Cambridge, UK), an update on algorithms from Dr. Claudio Cobelli (University of Padova, Italy), and Dr. Eyal Dassau’s comprehensive review of the “Artificial Pancreas database.” We believe more conversation among these groups is needed and we’re so glad to see this happening here.

3. Highlights from a stellar series of CGM presentations included new data on Medtronic’s fourth- and fifth-generation sensors, 90-day data on Senseonics implantable CGM, news that Arkray is developing its own 14-day CGM, and optimism that Roche’s novel CGM moving towards commercialization.

4. A series of talks on mHealth – including the developers of Nightscout – reinforced to us and many others that patient-centered/led design is not only possible, but necessary.

5. Dr. Bruce Bode (Atlanta Diabetes Associates, Atlanta, GA) was very positive on the results of Medtronic’s Op2tmise trial in his talk on insulin pump therapy in type 2 diabetes. In Q&A, he estimated that there are ~100,000-150,000 type 2 pumpers in the US. The power of better therapy for type 2 patients is enormous in terms of what it could mean for the bottom line.

6. Speakers humorously attacked the question of whether diabetes technology is better in the US or Europe. We heard notable commentary on limitations to CGM penetration and brief thoughts on the value of FreeStyle Libre.

7. Dr. Joyce Lee (University of Michigan, Ann Arbor, MI) gave an absolutely outstanding talk on the value of social media in diabetes, especially for the clinicians in the audience. Many said this was among the best they’d ever seen on this topic – we mightily agree.

8. Dr. Patrick Keith-Hynes (University of Virginia, Charlottesville, VA) delivered a forward-looking lecture on the potential of component artificial pancreas systems and wearable technologies (e.g., smartwatches) to augment closed-loop systems. 

9. MannKind CEO Mr. Al Mann’s keynote address discussed the inhaled insulin Afrezza, focusing on its ultra-rapid action profile and discussing hypoglycemia claims (or the lack thereof) on the approved product label. We continue to believe this could be a gamechanger for many, including various closed loop programs.

10. With the help of video and an on-screen user-interface, Mr. Steve Scott (Abbott Diabetes Care, Alameda, CA) gave a product demonstration of FreeStyle Libre.

Top Ten Highlights

1. An outstanding panel discussion on the Performance of Cleared Blood Glucose Monitors touched on a number of controversial issues ranging from the importance of BGM accuracy to industry and government perspectives on DTS’ Post-Market Surveillance Program. On the latter, the FDA’s Dr. Courtney Lias expressed the most enthusiasm we have heard to date from the Agency, including optimism that program will help the FDA make better use of limited surveillance resources – this is outstanding to see more partnerships and though we hope eventually FDA owns this program, we’d love to see more consensus building on this front. By contrast, industry perspective was more spilt on the utility of the program – Roche’s Mr. Rolf Hinzmann suggested that evidence documenting poorly performing meters already exists and that investing in subsequent testing without establishing clear consequences for manufacturers is “meaningless” – certainly we agree that the consequences need to be crystal clear. Abbott, Bayer, and J&J gave more measured feedback; overall, and none entirely saw eye-to-eye (which would be asking a great deal at this stage). Ultimately, the range of perspectives reinforced the complexity and intricacy of post-market surveillance and regulation – we are standing aside as to how this will move forward as funding remains a major issue and there is profound irony to the fact that far more resources are being asked of industry at a time when profitability has been decimated due to competitive bidding.

• The panel also provided new insight into the FDA’s ability to do something about inaccurate meter post-clearance. We had previously heard from FDA’s Dr. Courtney Lias that the process of pulling devices off the market is “pretty much impossible,” so we were very happy to hear more details on where enforcement may come from. This insight came from attorney Ms. Areta Kupchyk (Nixon Peabody LLP, Washington DC), who described the FDA's “rule-making" ability – e.g., the Agency could set a new mandatory accuracy standard for meters and prevent subpar products from remaining on the market. Dr. Lias lamented that the rule-making process typically takes “five to seven years.” To which Ms. Kupchyk replied, “Better get started!” Overall, Dr. Lias’ enthusiasm for this approach seemed quite low, and we’re note sure if it’s a viable solution.  

2. A provocative session entitled, “Controversies in Developing the Artificial Pancreas,” did not disappoint, with standout presentations from Drs. Claudio Cobelli (University of Padova, Italy), Ed Damiano (Boston University, MA), Eyal Dassau (University of California, Santa Barbara), and Roman Hovorka (University of Cambridge, UK). Dr. Damiano presented the latest interim results in seven patients from the ongoing Bionic Pancreas 11-day multi-center study (two additional patients from the five presented at CMHC 2014 in October). Average glucose has been 140 mg/dl (an A1c of ~6.5%) in those on the Bionic Pancreas, with just 0.4% of the time <60 mg/dl and 19% of time >180 mg/dl (although this was not discussed, we think Afrezza could reduce the >180 mg/dl significantly). Dr. Roman Hovorka (University Cambridge, UK) followed with discussion of strong outpatient results as well (previously presented this year), and very notably, a direct comparison of his team’s work to the Beacon Hill study of the Bionic Pancreas. Dr. Hovorka acknowledged the study differences, and implied that the addition of glucagon may not be adding benefits over insulin alone. He presented the comparison more as food for thought than as an attack on the MGH/BU team’s work. However, it was another reminder that the value of glucagon continues to be a controversy in artificial pancreas development. In particular, some have expressed concern that the Bionic Pancreas is too aggressive and does carry risks if the glucagon infusion set fails; we believe this is a critical point that will need to be addressed in longer studies, especially the planned pivotal study with a commercial-ready device and stable glucagon. It was unfortunate that Dr. Damiano was not available to engage in direct discussion on this – this is much of the value of these presentations and panels.

• Dr. Claudio Cobelli shared valuable updates in this session on new state-of-the-art algorithm work. Notably, he said that with Dexcom’s new G4AP algorithm (MARD: 9.0%; launched online last Thursday), “the glucose sensor is no longer a gating item” for the artificial pancreas. How amazing it was to see this, from a patient perspective, and once again we salute Dexcom for moving so fast and getting this through the FDA and into patients’ hands.
• Dr. Eyal Dassau provided a remarkable overview of closed-loop technology development to date. His presentation drew from the “Artificial Pancreas database” that the UCSB group has created by curating the past ten years of published clinical trials in the field.

3. On that note, a stellar CGM session featured next-gen technology in presentations from Medtronic, Dexcom, Abbott, Roche, Arkray, and Senseonics. Highlights included new data on Medtronic’s fourth- and fifth-generation sensors (MARDs of 12% and 8%, respectively in small studies); fresh 90-day data on Senseonics implantable CGM (MARD: 11.4%); news that Arkray is developing its own 14-day CGM based on Direct Electron Transfer (still early, but encouraging data in people without diabetes); and an update that new clinical data on Roche’s CGM will be shared in the next year as the company looks towards commercialization. Dexcom showed new clinical data on the performance of the new algorithm in pediatrics, demonstrating similar accuracy to that seen in adults. A talk on Abbott’s FreeStyle Libre did not offer any updates from those we saw at EASD; however a product demonstration later on (see #10) was a valuable reminder on its simplicity. In Q&A, Dr. Klonoff captured the strong session quite well: “I am extremely impressed. I cannot remember a better [CGM] session at any of the Diabetes Technology Meetings.” Detailed commentary on all company presentation is below.

4. A series of talks on mHealth – including the developers of Nightscout – gave us hope that patient-centered/led design is not only possible, but necessary. Dr. Joyce Lee (University of Michigan) devoted most of her presentation to Nightscout, allowing the founders to take the stage and explain the value of the crowdsourced CGM remote monitoring system – the audience was captivated as the Dads shared the profound impact this system has had on their peace of mind and family lives. Meanwhile, Dr. Joe Cafazzo (University of Toronto, Canada) gave a tremendous presentation on the critical importance of “empathy in design,” noting that he doesn’t see much of it health technology. He focused his presentation on an app called bant, which uses gamification and rewards to encourage good diabetes management. The team has tried to bring human factors and behavior change models to every aspect of the app. A new version is now in a randomized controlled trial in type 1 adolescents, and a product for type 2 diabetes is also in development. The last highlight of this session came from FDA’s Dr. Beth Stephen, who discussed the Agency’s role in mobile health. Of note, she said that “diabetes-related interoperability is a high priority” for the Agency – it will be most valuable to hear a whole morning session on this topic at Wednesday’s Public Workshop: “Regulatory Science Considerations for Software Used in Diabetes Management.”

5. Dr. Bruce Bode (Atlanta Diabetes Associates, Atlanta, GA) focused on Medtronic’s Op2tmise trial (published in the Lancet in July) in his talk on insulin pump therapy in type 2 diabetes. He was very positive on the trial results: “Clearly, for pump therapy in type 2 diabetes based on Opt2mise, if you’re failing MDI, you’ll do better on a pump, with less insulin, a significant drop in A1c, and no increase in weight or hypoglycemia.” In Q&A, Dr. Bode estimated that there are ~100,000-150,000 type 2 pumpers in the US, which has grown dramatically from ~35,000 six-to-eight  years ago (and his estimate of 50,000-100,000 at CDTM 2012) – while there is no way to know exactly how many type 2 pumpers there are, it was interesting to hear this estimate. Notably, Dr. Bode said he has heard that ~30% of pumps now sold in the US are for type 2s. More of Dr. Bode’s commentary on Opt2mise and insulin delivery in type 2 is below.

6. In a provocatively titled debate, speakers humorously attacked the question of whether diabetes technology is better in the US or Europe. Drs. Hans DeVries (Academic Medical Center, Amsterdam, The Netherlands) and Barry Ginsberg (Diabetes Technology Consultants, Wyckoff, NJ) delivered two of the most entertaining lectures of the entire conference. Using a points scheme, Dr. Ginsberg quantitatively assessed whether the US or Europe has contributed more significantly to innovation, giving the edge to the US. Dr. DeVries gave a more even split between the US and Europe on diabetes technology, but comically concluded, “Diabetes technology is perhaps slightly better or worse in the US, but many other things are better in the EU.”

• In Q&A, panelists offered more substance in response to a query on the future of CGM. Dr. Ginsberg described the three limitations to CGM penetration in his view: (i) accuracy; (ii) cost; and (iii) overwhelming data. He acknowledged that accuracy continues to improve, though data overload and cost remain relevant issues. On the latter, Dr. DeVries highlighted the launch of Abbott’s FreeStyle Libre as a low-cost alternative – “In my opinion, it’s a CGM...[but] less than 50% of the price of CGM.”

7. Dr. Joyce Lee (University of Michigan, Ann Arbor, MI) gave an absolutely outstanding talk on the value of social media in diabetes, especially for the clinicians in the audience. Primarily through the lens of Twitter, she made a persuasive case that social media IS diabetes technology – it is disseminating tools (e.g., Nightscout, DIY Artificial Pancreas), helping patients troubleshoot, providing patient input to product design, facilitating conversation (#DSMA), sharing useful information, facilitating advocacy (#DOCAsksFDA), and even “saving lives” (in the words of Kerri Sparling). “If we’re not there [as clinicians],” Dr. Lee implored the audience, “there’s a huge piece of the pie that is missing.” At minimum, she believes it is an obligation for healthcare providers “to lurk, listen, and learn” online. This was one of the strongest and most persuasive cases we’ve ever seen on the value of social media in diabetes – we give sincere congratulations to Dr. Lee for being so forward-thinking (she has tweeted over 21,000 times!) and such a great advocate for the Diabetes Online Community (DOC). 

8. Dr. Patrick Keith-Hynes (UVA, Charlottesville, VA) delivered a futuristic lecture on component artificial pancreas (AP) systems and the potential addition of smartwatches. He explained that component AP systems distribute signal processing among the CGM, the pump, and an external controller such that if any component fails, the system can degrade peacefully and keep patients safe. According to Dr. Keith-Hynes, such systems are hugely advantageous for multiple reasons, such as: (i) they reduce the regulatory burden on the controller, enabling rapid iteration and improvement of the algorithm, and (ii) they place the algorithm outside the pump, giving it access to new types of sensor data (such as biometric information generated by wearable technologies). Indeed, Dr. Keith-Hynes characterized unobtrusive wearables as solutions for the future of closed-loop technology as they minimize device burden and improve adherence by giving patients a gadget they “want to wear.” See below for detailed commentary and a neat glimpse at already ongoing efforts to integrate UVA’s DiAs closed-loop system with the Moto 360 Smartwatch.

9. Dr. David Klonoff introduced the morning’s keynote address with one simple message: “Don’t bet against Al Mann.” Taking the podium, MannKind CEO Mr. Al Mann presented on the inhaled insulin Afrezza, focusing on its ultra-rapid profile. Although the product label recommends dosing Afrezza at the beginning of a meal, Mr. Mann suggested that the onset of action is so fast that aiming for 15-20 minutes following the start of the meal might provide better postprandial coverage. He also discussed the possibility of using two or even three doses to cover longer meals, although he acknowledged that new dosing patterns would need to be validated in clinical trials before getting added to the product label. Mr. Mann explained how Afrezza’s ultra-rapid action had the counterintuitive effect of improving glycemic control without decreasing A1c, which is in part attributable to the reduction in postprandial hypoglycemia. The FDA either did not appreciate this nuance or did not find the data compelling enough, which partially explains why there was no mention of a hypoglycemia advantage in the product label – read our report on Afrezza’s approval for more background on this issue.  

• Intriguingly, Dr. Klonoff followed by mentioning that the Diabetes Technology Society has plans to push for a broader range of possible primary endpoints, beyond A1c, in clinical programs for new diabetes therapies. He agreed that it was unfortunate that Afrezza did not receive due appreciation for its reduction in postprandial glucose because of the lack of a consistent improvement in A1c. Decreases in hypoglycemia and severe hypoglycemia as well as improvements in time in range, in his view, are some of the other clinically meaningful outcomes that should be considered as possible primary endpoints – we wholeheartedly agree, as we discussed in our presentation at the FDA last Monday. Dr. Klonoff encouraged individuals or groups that are interested in this topic area to get in touch with DTS.

10. With the help of video and an on-screen user-interface, Mr. Steve Scott (Abbott Diabetes Care, Alameda, CA) gave a valuable product demonstration of FreeStyle Libre. The videos showed product setup, sensor application, startup, glucose scanning, and sensor removal – all served as a great reminder of just how user-friendly and out-of-the-box ready the product is. The user interface demo focused on the on-device reader menus and reports, which include time-in-target, a logbook, ambulatory glucose profile (AGP) reports, and more. This presentation was much more polished and consumer friendly than in the debut at EASD 2014, which focused much more on the accuracy trial results. Though FDA was in the room, Mr. Scott did not offer further details on the US pivotal study or an FDA submission – as of EASD, the US pivotal study was expected to begin before the end of 2014. He did say, as expected, that Abbott will try to pursue a replacement claim for the product (which it was not able to get for FreeStyle Navigator in the US). In Europe, FreeStyle Libre launched in October at web-shops online.

Detailed Discussion & Commentary

Performance of Cleared Blood Glucose Monitors – What is Needed

Panel Discussion

Dr. David Klonoff: The questions we have to address are: (1) Do current cleared BGMs produce adequate data? Are they adequately safe for patients? (2) If they are not good enough, what is best solution? (3) If we have a proper solution, how can we best engage the diabetes community (patients, HCPs, payers, industry, and regulators)?

Dr. Alan Cariski (LifeScan, Fremont, CA): Meters that meet the 2003 ISO standards have been used in studies and have been shown to be safe and effective to get people to goal. The question is whether all meters safe and effective. Dr. Freckmann did an excellent study that showed a number of meters don’t meet the 2003 standard. You might ask, “How could Dr. Freckmann use the ISO 2013 standard for a 2012 study?” Well in 2012, the ISO 2013 standards were pretty much set and didn’t change. That standard is supposed to represent the state of art, and has a three-year transition period build in. Dr. Freckmann’s study showed that not all manufacturers are producing to that standard. The fact that 50% of meters didn’t meet the 2013 standard isn’t a concern to me – ISO 2003 was the standard in place at the time those meters were cleared. The standard reflects the state of the art – I think the 2003 standard was not unreasonable, and the 2013 standard is even tighter. Meters meeting that standard will be safe and effective.

Dr. Rolf Hinzmann (Roche Diagnostics GmbH, Mannheim, Germany): Speaking for Roche, I can say that we are committed to the highest quality standards. We have developed methods to ensure that Roche meters meet and exceed the highest standards. Our quality assurance procedures compare performance against ISO 2013, but also use very sophisticated in-house procedures. Many groups, including Dr. Freckmann’s who is sitting to my right, have demonstrated this accuracy. I would also like to add that we have established a system of traceability for our meters. This means that BGMs by Roche are traceable to the highest metrological method, isotope dilution mass spectrometry. We are running one of these systems in Mannheim; this is one of a handful of labs that is accredited for this purpose in the world. We’re the only company that is using this method in Germany that is credited by the German government. We are doing everything we can do to ensure that patients who receive Roche devices are going to get safe and effective readings. That said, we are very concerned that this is not true for all patients. We can see that there are manufacturers who do not consistently fulfill these standards. It’s a pity that these devices are still given to patients.

Dr. Robert Vigersky (Walter Reed National Military Medical Center, Bethesda, MD): I would like to point out something in the way you phrased the question that I thought was very clever. All these meters that have been approved were adequate at the time when they were approved. The issue, which is what Dr. Freckmann showed, is what happens to the quality of the strips and measurement thereafter. It’s important to point out that Dr. Freckmann took the meters and strips off the shelf, and that the manufacturer did not provide them. It is important to differentiate between what happens during registrational trials when the FDA is clearing the meter vs. what is happening in the real world.

Dr. Klonoff: Why do you think the results would be different in the real world?

Dr. Vigersky: I’m sure there are many potential reasons: the way the strips are handled in their transportation to the end user, the handling of the strip shipments by many people, or exposure to heat and humidity. Certainly there are potential errors that happen in the manufacturing process itself that may not be caught in an evaluation of the lot release. In the end, if half of meters don’t meet standards when used in the real world, then we have a problem.

Dr. Boris Kovatchev (UVA, Charlottesville, VA): Meters provide good data and analytical information. I want to take a risk and say that there is a big difference between data and information. We know that from papers in various investigations that about half of meters provide good data under recently established standards. But very few, if any, extract adequate information. If we make this distinction, we must acknowledge that accuracy is important. But we should also keep in mind that we should focus on analytics and data that will turn data into actionable information. Information is relevant to long-term use of data and trends.

Dr. Ricardo Perfetti (Sanofi, Bridgewater, NJ): I’d like to echo what was just said. I’m asking myself, “How much of the information there is used?” I’m wondering whether there is a primordial problem greater than the accuracy piece. We need to place data into the context of information. I think the level of translating information into action is so limited, that it’s an even bigger problem for me. That’s not to disregard accuracy as a centerpiece. But still today, we have a meter number often not used by patients or physicians. Accuracy is important for an n=1 study; but on a population basis, most critical is the use of information.

Dr. David Klonoff: I heard you say, Ricardo, that we’re not extracting enough information out of blood glucose monitors. Does anyone feel that if we can inspire better use of BGM then we would be in a position where we could acknowledge that they are not as accurate as they should be but that we’re getting the benefit through some other method?

Dr. Vigersky: I don’t think we can ignore the importance of accuracy. I understand the consideration here. However, I’m an adult endocrinologist, and I see patients all the time. We need them to be “n of 1” accurate. We had a meeting here in Bethesda a few days ago where we heard from a panel of patients who talked about accuracy. This was part of the DTS Payer’s Meeting. These patients got up on the panel, and it was really, I would say, amazing to hear how much they rely on their meters and how important the accuracy of those meters is. One patient actually said that a half-unit difference in her insulin makes a difference in whether she becomes hypoglycemic. Such a small difference means so much. Every one of those patients made clear that they rely on the accuracy of meter on a day-to-day basis. These are patients who are extracting vital information from blood glucose data. I would say that that is true for enough of our patients that accuracy becomes the major issue when talking about this.

Dr. Steve Scott (Abbott Diabetes Care, Alameda, CA): I think the issue is to ensure that there is a responsibility on us that in a real-world situation, these meters continue to meet standards.

Dr. Jane Chiang (ADA, Alexandria, VA): On behalf of ADA, we believe that in aggregate, meters’ accuracy is largely sufficient. The one area where we could do a better job is in the lower range. An error of 20% is not as significant if your glucose levels are at 150 mg/dl than if it is at 70 mg/dl. As a pediatric endocrinologist, the margin of error at lower ranges is critical.

Mr. Markus Ott (Bayer, Basel, Switzerland): Accuracy matters. When ISO changed, that’s all about accuracy. Accuracy must matter. Companies that are quality driven like Bayer do everything possible so that our product will perform, but that adds to cost as well. The quality standards in place are not free, but some manufacturers out there do not have standards. Any manufacturer out there can provide perfect samples for testing. So any program out there that could collect samples and test them would be useful.

Dr. Hinzmann: I would like to respectfully disagree with the previous statement that the systems out there have sufficient accuracy in the hypoglycemic range. I would say that some do, but some don’t. The consequences of a system that isn’t accurate have been shown in many studies. All these papers are out in the public. Unfortunately, the clinical community often ignores them. I think it is of the utmost important that BGM are accurate, because if they are not, then you are missing hypoglycemia. You are inducing hypoglycemia if you are mis-dosing insulin because of inaccurate readings. You are increasing A1c over the long term. These are all such negative side effects that we cannot afford inaccurate meters. It’s important to identify and distinguish which are the meters that do perform and do not perform.

Dr. Courtney Lias (FDA, Silver Spring, MD): I wanted to say that we’ve heard at FDA that there is concern about the performance of meters at the hypoglycemic range. That is one of the big points we were trying to get changed in the 2013 ISO document, which unfortunately did not move forward into the current version. The requirements in the hypoglycemic range in the ISO 2013 document did not really change or improve. On the FDA’s part, we get very little data on products in the hypoglycemic range. If you test only according to ISO standards, it’s difficult to tell how meters will perform in the hypoglycemic range in the real world. With hypoglycemia being a major patient concern, we can do better in that range. In guidance documents, we’re trying to propose a little more data collection in that range – to tighten that a little bit. We’re looking at the comments we’ve received to see what stage we are at, but we hear real concern from patients about having accurate information on their blood sugar before they get into a car or go to bed.

Dr. Robert Vigersky: I just want to add on to something Jane said. I agree that it’s very important to have accuracy in hypoglycemia. You said accuracy at 150 mg/dl is not so important, but it is quite important. A 20% error at 150 mg/dl reads 180 instead of 150. You might give two units of insulin instead of one. If one unit drops you by 50 mg/dl, you’ll drop from 150 to 50 mg/dl, and cause hypoglycemia. Even in the mid-100 mg/dl range, it’s very important to have accurate readings – you’ll have major errors. A study was published in 2007 that examined the real-world insulin mis-dosing that results from inaccurate meters. The study took patients from three different clinics, gave patients an insulin tolerance test, and documented how they would dose insulin. These dosings were affected by inaccurate BGM readings. Depending on the meter, 35-45% of patients would wrongly dose of insulin by ~1 unit. That was in 2007, but that is equally applicable now.

Dr. Guido Freckmann (Institute for Diabetes Technology, Ulm, Germany): In response to the question of whether we have good meters available, I would say that we do, but that there is still a lot of variation. Testing to the old ISO standard only meets the minimal criteria. Variation between devices, and between devices and the reference, is a problem. If patients are using devices from different manufacturers, then this is a big problem. Accuracy at the low range is really a problem for many devices. We published a poster at ATTD this year in which we tested four devices, received 200 values below 70 mg/dl, and there were some big differences between devices.

Dr. Klonoff: Guido has more experience doing post-market surveillance than any independent investigator in the world.

Dr. Perfetti: I agree on some of the practical examples that were just made. The marginal dose change that could be catastrophic is obviously a major concern. There is a value of the dose of insulin and the A1c. In China, the average insulin dose is 16 units per day, and the mean A1c is in the low 9% range. In France, the average insulin dose is 23 units per day and the average A1c is in the low 8% range. Part of this is that people do not measure. The people that come to see a specialist do measure. But the large majority of patients don’t see a specialist. They are not educated on the importance of using meter. Accuracy is a must, a pre-requisite. But this is a bubble, and the problem is even greater than accuracy.

Ms. Areta Kupchyk (Nixon Peabody LLP, Washington, DC): The question that comes to mind is what would this mean if a company was sued for their product not being accurate. What would be the risk? I think there’s a lot of evidence that accuracy is a question, simply because of the lack of post-market surveillance. However, there are a lot of different factors that go into whether there is an accurate result, such as user error, the environment, etc. As a lawyer, if I were representing a patient, I would have all that laid out. Accuracy is a huge issue, but you also have all those issues to contend with.

Dr. Klonoff: We’ve gotten a variety of comments that have addressed not whether current meters perform according to standard for which they were approved, but according to standards that are adequate analytically and clinically. I would say that the majority of comments I’m hearing are that not all blood glucose meters are performing as accurately as they should be.

Let’s go on to the second topic: if you believe that meters are not performing adequately in terms of analytical accuracy or clinical safety, what should we do? Speaking for the Diabetes Technology Society, what we are likely to do is start the DTS Surveillance Program. Do people have other ideas?

Mr. Ott: It might be that nobody has the answer today. We have seen all the studies out there, but we don’t see any action from authorities. The meters that were tested as inaccurate are still being exposed, and are still being used by patients, to unknown effect. We must work jointly on a solution. I think testing meters is definitely the right way to go. 

Dr. Lias: Many of you know, one of the FDA’s responsibilities is ensuring that products on the market perform as they should perform and that they meet the standards by which they were cleared. However, we are aware of the growing evidence that manufacturers are not producing lots that meet the standards by which they were cleared, and we do have activities ongoing to assess these situations. We have inspections ongoing. These are typically directed inspections where we act on information that we have. However, I can tell you this is challenging especially when companies are spread around world. Our ability to monitor companies in different countries varies as the rules in some countries can be different from those in the US. However, we do find things, and we do take action. Those actions are not always public. We do take a lot of actions in these areas and have had companies make a lot of corrections. That said, there is still a lot of work to do. At the FDA, we are trying to take many steps in a positive direction. In our proposed 2014 draft guidance on BGM accuracy, there is a clause for manufacturers to submit information on test strip lot criteria during the pre-market phase. This won’t prevent all the problems we are having, but it should help. For example, now if we go in and find that manufacturers have modified their test strip lot criteria later on without a good reason, then we have more of a case to say that they acted in bad faith. All these things require evidence gathering though. With more resources, we can do a better job. This is where the DTS Surveillance Program comes in. We like the fact that the program is independent, is going to be credibly done, and is going to reflect the real-world accuracy that consumers see when they buy meters in pharmacies, etc. This program can help focus our resources to the places where they are really needed. It won’t solve all our problems, but it will give us the tools to solve problems better.

Dr. Scott: What I wanted to say is that we, at Abbott, are proud of the strips that we make. We welcome an opportunity where there is post-marketing surveillance to demonstrate what our products can do in the real world, in patients’ hands, and that the quality is maintained through the life of the product.

Dr. Klonoff: We’re hearing from the panelists from companies that they are producing high quality products, and that they are proud of their products. Just so you know, we’re frequently approached by these companies, and they all have the same message: “we’re big companies, and we go out and buy glucose monitors from our large and small competitors to see how we stack up against the competition. I have to tell you that the other big guys are good. A lot of the little companies are good, but some are bad.” The big companies have said positive things like that about their large competitors – we haven’t heard anyone come to us about the large companies’ quality. If you’re wondering why you’re only seeing five big companies here, it’s because these are the companies that have approached us. If you are a small company and are doing the same thing – comparing your quality to your competitors’ – we’d love to hear from you.

Dr. Cariski: I agree – the major manufacturers have excellent quality controls. They manufacture their products very carefully and have agreements with the distributors that handle products as they leave facilities. Strips won’t be stored in conditions that make them deteriorate. At LifeScan, we also think that there are lots of signals that the regulators can use to help determine which companies merit a focused review. For example, Dr. Freckmann has published studies on review procedures. Although they may not represent the kind of body Dr. Klonoff is trying to create, reputable investigators conducted the work, and the problem identified in this study at least warrants investigation by a regulatory agency. Roche did a five-year study and found that 25 manufacturers had not submitted even one medical device report to FDA. It is inconceivable that those manufacturers did not receive complaints. Complete absence of MDR reports over a reasonable period of time is a good reason to trigger an investigation, or at least suggests that the manufacturer does not have a credible quality assurance system. I would say that is prima facie that their product cannot be relied on to be good.

Dr. Lias: The only way to get that information is to do inspections. We don’t have the resources to focus our attention. For example, let’s say there are 10 companies making meters, but only five of them are making poorly performing meters. The problem is that we only have resources for five inspections, and we want to go after those five companies first. That’s where the DTS Surveillance Program would help.

Dr. Ott: There seems to be a place for this type of testing. In the countries that have surveillance leading to restrictions on marketing, only a fraction of the meters marketed in other countries and in the US are on the market in these countries. For me, that is an indication that we are going in the right direction if we do post-marketing surveillance, and that we have a tailwind for moving forward.

Dr. Lias: I agree, and resources are an issue for any government. If we had a program that published its results, it would be a deterrent to do those practices. It’s not just something that catches people, but it may also prevent people from taking some of those risks, which could benefit patients.

Dr. Chiang: One of my roles is to represent the patient perspective. I hear everything that companies are saying. Patients get meters that are not from larger companies due to the cost differential. Accuracy is important, but we must address the cost differential, because cost is a big concern for people with diabetes. Until we are able to prove that these devices are substantially inferior, patients will continue using them.

Dr. Klonoff: What type of data are patients looking for?

Dr. Chiang: Anecdotally, if a meter is roughly within the ballpark of 20% to 25%, some patients will say that’s okay for them. For a lot of people, there is a huge price differential, and they’d rather check their blood glucose on any meter than not check. As we’re moving forward with accuracy discussions, I think we need to keep the issue of cost in mind.

Dr. Vigersky: The question you raised, Dr. Klonoff, is what the solution to the problem of inaccurate meters is. The Diabetes Technology Society has come up with a wonderful solution. I’m going to throw out a thought experiment as another possible solution. I’ll draw an analogy to our cars: we’re obligated, if we want to drive a vehicle, to go in for inspections on a regular basis. If the car fails, we can’t renew our registration. Why don’t we have inspection stations for glucose meters? Maybe the ADA can set up a series of these stations around the country, where people can bring their meters and have them tested for accuracy. Maybe both types of solution, a broad policy and one that works on an individual level, would be good to have.

Dr. Hinzmann: I want to make two points. First of all, it’s tempting to say, “Let’s create more evidence.” But, in my mind, this is only postponing the problem. The evidence is there. We must make use of it. These studies have been conducted and are out there. They are just not widely known. Creating evidence is only useful if there are consequences for manufacturers who don’t meet these standards. As long as this is not defined, it is meaningless to have more evidence. We can act upon the evidence we have already. We can bring this evidence to light. At every diabetes conference, at every conference of diabetes nurses, at every conference of patients, of every conference of clinicians, we must raise the conversation about accuracy. Some people think this topic is boring. Some people think accuracy is not a problem. My recommendation is to act on the information we have and to educate people about accuracy.

Dr. Lias: It depends on the type of evidence. Patients are more likely to be reading Consumer Reports than to be reading scientific papers. If you’re talking about the evidence that is already out there, you have to do some education to get people to value it. The evidence out there is not the evidence we need to take action against companies – it’s not that level of evidence. Then you need the level of evidence a payer might need to make a different coverage decision. All of those things are different.

Dr. Kupchyk: Finally this is something I know about: evidence. Evidence is made up of facts. If you have facts, you have evidence, but if you don’t have facts, you still have evidence, because the absence of facts says something. Right now, if you don’t have enough information and if you can gather more evidence, then you should. The lack of information therefore means that you are not doing what you’re supposed to be doing. If I was on the other side, from the patient perspective, I would say that you should have gotten more information on how to make your product better. You’re capable of doing it, you should have asked more questions, and therefore you are responsible. In some ways, that is how the FDA looks at it. It is the company’s responsibility to create and produce safe products that work every time. Evidence is relative: it depends on who’s asking for it, who needs it, what’s out there, and what isn’t. We’re in a situation where not pursuing evidence is going to put everyone in a bad, vulnerable place.

Dr. Klonoff: I’d like to ask a question of Courtney based on something I heard Jane mention. This notion that some people think it is OK, in some cases, to use products that are not up to FDA specification for good reasons. Thoughts?

Dr. Lias: I don’t think patients think about whether a product is up to FDA specifications. Jane, I think, made a good point. If someone values more testing more often every day, then they may accept some financial tradeoff. Whether they understand that tradeoff is another question. I can understand that. However, I want to ensure that they don’t have to make that tradeoff.

Ms. Kupchyk: It seems there should be a minimum that every company has to meet. Even if someone cannot afford top of the line, they should assured that products meet a minimum standard.

Mr. Ott: We may have enough evidence, but the evidence must be interpreted in context of the purpose. For example, the value of testing in non-insulin-treated type 2 diabetes depends on what studies you reference. You could take DIAGEM, PRISMA, STeP, or take a totally different study, and would come to a different picture. Do we have the right evidence? We also need fair standards – the right standards. There needs to be standardization, not only by one stakeholder. We need to test with this kind of purpose, and you can only do that if something is standardized to some extent.

Dr. Lias: There are publications out there, and they are often done in different ways. In a court of law, if we were trying to bring a publication against a company in which the device didn’t perform well, the company will come to the judge with a study in which it did well. There will then be questions about who funded the study, whether the studies were in favor of whoever funded it. Though I happen to believe that there is a problem, you can poke holes in anything unless you try to develop evidence in a way that is as airtight as possible.

Dr. Cariski: I want to take a moment to reinforce what Rolf said about the fact that there is evidence already regarding poorly performing meters. I don’t believe that Rolf is suggesting that based on the evidence the FDA or other regulatory agency can reasonably ask manufacturers to remove a product from the market. However, what the evidence does suggest is that the FDA can do an inspection. Isn’t this what would be the outcome of David’s program? He is going to identify poorly performing meters, and then it would be up to the agency to inspect manufacturing facilities to see whether issues exist. It’s not about who identifies problem. That said, it’s also not just about one lot. One cannot assume that all other lots are of poor quality because of one poor lot. The FDA does have well-trained inspectors who look at quality system, and it’s quite an event when they do an analysis. They find problems. They’ve found a lot of things.

Dr. Klonoff: We agree, and we view our program as one that generates signal information. We don’t intent to be a substitution for clearance, and are not saying that if you pass our program you should be cleared, and if not you should be taken off the market. That is the FDA’s role. We’re not going to be testing to that degree – it’s testing to raise a signal. We’ve recognized that there is a problem and there are solutions. To what extent do we need to be engaging others, beyond this panel? Before going to the panel, we will open this up to the floor.

Dr. Lutz Heinemann (Profil Institute, Neuss, Germany): When we talk about who is not engaged, I’m happy to see someone from ADA on the panel. My personal perception is that ADA and EASD have ignored diabetes technology and blood glucose meters for quite a while. Not too many presentations at ADA and EASD have focused on this. I regard this discussion as clinically highly relevant. The associations should be more active. I’m personally active in a committee established by ADA/EASD to tackle such questions, but I see a need for them to be more active and have more open discussions about things like this.

Dr. Chiang: I agree with you that in the past we’ve been more reticent to talk about this. One of the reasons people say that the ADA should be part of the discussion is related to reimbursement. However, at the ADA, we do not have the resources to tackle reimbursement as much as providers would like us to do. Regarding meters and accuracy and availability, it is difficult to take a position on what we endorsed. Overall, we endorse safe, accurate, and cost-effective meters for people with diabetes. Now, remember, most people with diabetes have type 2 and some of them have very limited resources. So with that in mind, when we talk about our recommendations for meters in general, we can’t take a position. We can only say we believe in safe, effective, and cost-effective meters. We are working with the EASD on the technology part. You’re right though. We have more to do.

Dr. Barry Ginsberg (Diabetes Technology Consultants, Wyckoff, NJ): I wonder if we’re not approaching this from the wrong direction. Handling this with a regulatory approach means that we are ready to accept the pre-2003 standard, meaning that products that were approved under the 2003 standard would only have to meet the standard they were approved under at the time. If you want more accuracy, and you want payers to urge it, the only approach is to use a public affairs approach. That would mean saying that we have data on some meters, but not others. It will be important to get the press and public involved – to create a groundswell through which you can nudge the payers in the direction you want.

Dr. Klonoff: To address something that you said, we at DTS feel that the 2003 ISO standards are not really good enough, and we don’t feel constrained to have that as the passing score. There is no reason why we can’t demand something tighter, maybe the 2013 ISO standards or the FDA standards. I don’t think that anyone should expect that our goal is to just get meters up to the 2003 standards.

Dr. Ginsberg: Well don’t expect the regulatory approach to work like that: if meters met the standards that they were approved under, then they are fine from the regulatory point of view.

Dr. Klonoff: Well according to literature, 25% of monitors don’t even meet the 2003 standards. If all that we got out of this was to identify the 25% of meters that are not performing accurately as per the 2003 standards and that don’t deserve our good graces, then that would still be a good thing.

Dr. Lias: There are very few meters that are still out there from 2003.

Dr. Kupchyk: There is a question of a new standard replacing an old standard. What happens to products on the market that met old standards? If the change in standard is for safety, why should products that don’t meet the standard stay on the market? That’s the toughest thing for FDA to grapple with. The agency could inform everyone in the industry that by the end of the year, if you don’t meet the standard, you’re off the market. We haven’t seen that kind of aggressive approach yet by the FDA.

Dr. Klonoff: Are you saying that that’s a tool the FDA has? To say you have until the end of the year to meet standards, or else?

Ms. Kupchyk: Well, the FDA can’t say anything they want. However, there’s a basis for demanding improvement and setting a standard if that basis is safety for patients. You can make an argument that meters that don’t meet standards are endangering patients because there are better products out there. Even if the FDA does not take legal action, I could take them to court, as a patient, under state law and say that companies are knowingly manufacturing subpar and unsafe products. The FDA is in position to say, with fair warning, that everybody has to meet a particular standard. You can give companies an opportunity to comment on it and give their feedback. Once everybody comments, then the FDA can set a deadline and say you’ve got this much time to get your act together and if you don’t you have to get out of the market. This would probably take some time. The fact is that the FDA has not been very good that this, historically. There are all kinds of products on the market right now, not just in the diabetes field, that shouldn’t be. This is partially because the FDA doesn’t have the resources to do this. And so, if this were done, there would probably still be about two or three poorly performing products out there. But yes, the FDA can make that happen.

Dr. Lias: She’s right. It typically takes five to seven years to do that though.

Mr. Scott: While we’re on the topic of standards, the ISO 2013 standards do come with a legal requirement that applies in Europe that three years post-publication, a company can’t put something onto the market that does not meet those standards. My impression is that the organizations at this table will move to that standard even before then, but I wanted to remind you that there is a legal requirement to meet the new standard in Europe.

Q: I’d like to briefly address risk people correcting hyperglycemia – risk increases in the high range, and the lower your target, the greater your risk.

Dr. Klonoff: I don’t think anybody disagrees with you up here. The title of this session is specifically the performance of glucose monitors. That’s why we’re focusing on performance. In terms of what is needed in a non-performance sense, those are good points.

Dr. Hinzmann: An argument that you hear often is that the accuracy of blood glucose meters is not so important because there are other errors being made by patients. For example, some patients have no idea about their insulin sensitivity, or don’t do proper carb counting. This argument is logically wrong, because errors are additive. Errors of carb counting or insulin sensitivity add on in a mathematical way, adding to the analytical error. They do not compensate. Therefore, accuracy is important.

Q: When conducting glucose measurements, there are two components to take into consideration in my view. One is the device. The other is the user and all the factors that come with the user. The point is that there should be a balance between the two. Unfortunately, the panel – although there were some remarks about users – commented generally on device errors with respect to performance. I’d like to get back to users. The title of this discussion was “Blood Glucose Monitors – What is Needed?” I’d recommend changing the title to “Blood Glucose Monitoring? What is Needed?” Even then, I’d say that two important issues come to mind. For one, we need an increase in the use of devices, because patients don’t use them for a variety of reasons. The other issue is that we need to reduce the impact of errors caused by users. On top of that, I’d also mention that there is a difference between the needs of type 1 and type 2, insulin-treated and non-insulin treated diabetics, and we have to take that into consideration.

Dr. Klonoff: I’m hearing comments that there is more to glucose monitoring than analytical performance. It’s just that it’s so hard to get something done in this world that we are focusing on performance for now. That is not to say that other factors aren’t also important. In the future, we’ll probably address some of those other factors specifically.

Dr. Kenneth Ward (OHSU, Portland OR): I have a methods question. If you’re going to test and compare 10 different meters, how many strip lots do you use? And do you have trained technicians do those tests, or people with type 1 diabetes?

Dr. Klonoff: We have to try to test and treat every meter equally, which would determine how many strip lots we would test. As far as the standards and how accurate they need to be, the steering committee is going to make that decision. They are experts in glucose monitoring and surveillance. We have the top professional organizations dealing with diabetes: AACC, AADE, ADA, CAP, The Endocrine Society, JDRF, plus representatives from serious government agencies like FDA, US Army, NIH, and CDC. Any target that we aim for could be questioned; there is no number that is going to satisfy everybody, but we will do the best we can. The next important question is: how expensive is it? If these findings were to compel a decision by the FDA and government, we would need a tight confidence interval. Getting all the data would be very costly. To create a signal that everybody feels a signal, in that it is very likely, costs just a fraction of that. It’s a waste of money to come up with a new gold standard for everyone – ultimately it is how the FDA wants to act on the finding that matters.

Dr. Dorian Liepmann (University of California at Berkeley): I was surprised to see that Consumer Reports does rank meters. They have ratings of around 25 meters, and all met the 15% guidelines, and they do tests of accuracy, repeatability, and precision.

Dr. Chiang: The ADA also does ratings of many meters in our Diabetes Forecast January issue, which is a popular issue. We don’t come out and recommend one meter over others, but we do provide objective guidance. We don’t have the resources to do true tests of analytical accuracy.

Dr. Bruce Buckingham (Stanford University, Stanford, CA): I would disagree with your praise of the Consumer Reports data – the second top rated meter on their list ended up being quite variable when we tested it. Subsequently it was taken off the market.

Comment: I’m an endocrinologist in inner city Baltimore. The population I see tends to be patients on Medicare, Medicaid, and a lot of underinsured patients. What I’ve noticed is that some patients are required by their plans to use poor meters. So I would say that we need more pressure on payers to cover better quality meters.

Dr. Klonoff: Thank you. That was one of the themes of the Payer’s Meeting we held on Wednesday. We talked about strategies to engage payers.

Dr. Klonoff: Let’s take brief summary comments from each panelist.

Dr. Cariski: There are about 20 billion BGM tests performed worldwide annually. While there is probably substantial under-reporting of adverse events, not every adverse event is reported. Sometimes it is impossible to know. I think one of reasons why patients are able to use good meters with good results is that variability isn’t plus-or-minus 20%; that it’s not 70 mg/dl today and 130 mg/dl tomorrow. For individual patients, variability is usually about 6-7%. Another point, in general, the calculations regarding insulin sensitivity and correction factor are based on the meter. When a meter gives results of 200 mg/dl while the real result is 240 mg/dl, patients bake that inaccuracy into calculations for insulin sensitivity and correction factors. Precise meters used properly are how people are able to regulate their diabetes. We don’t see the level of adverse events that you would expect to see with 20 billion tests annually.

Dr. Chiang: My final thought is that we need to think about “currency.” I’m guessing that most of the people here in this room are very homogenous. Patients do not see things the same way we do. So the “currency” of patients needs to be considered. The patient needs to be a part of these discussions, because what they value may be different from what we value. And when I say patients, I mean healthcare providers as well. The other stakeholder I would add to this conversation are the payers. They are also very important to include in this discussion. I was at a recent bariatric surgery conference that involved payers, and it was clear that the way they saw reimbursement was so different from the way patients and healthcare providers saw it. So, we need to think about the “currency” of every stakeholder: payers, patients, providers, industry, etc.

Dr. Hinzmann: At Roche, we are open to any initiative that improves patient safety, but we want it to be impactful. Sending out signals to the FDA or the public is not enough. We think there are three requirements for the program to be successful: it must be obligatory for all manufacturers, it must be fit for purpose to distinguish between companies that are performing and those that are not, and there must be clear consequences. Only if post-marketing surveillance can provide these features will it have a direct impact on patient safety, and make being a diabetes patient a bit better.

Dr. Freckmann: Patients, physicians, FDA, and companies will react to published data from a post-market surveillance program that tests random lots. Having glucose meter accuracy data available will change a lot of things.

Dr. Lias: One thing I want everyone to keep in mind is that we believe that BGM has made patients lives better over the past 20 years. I would never go back to a state without BGM. We’re doing everything we can to improve patient experience with BGM as much as we can. And we look forward to seeing if there are tools that can help us improve patients’ experience going forward.

Dr. Kupchyk: The thought that strikes me is that we have the new 2013 ISO standards, and we need to figure out how to get everyone up to that standard. Lawyers current play the role through suing people. It’s not a very effective way to do it. The FDA is probably in the best and most effective position to work on this, as well as industry and patients.

Dr. Kovatchev: The general public and payers don’t understand that accuracy is important. Until they understand, various other factors and other considerations will get in way of the technology, like cost. I think it’s a bad thing they don’t understand that accuracy matters.

Dr. Ott: We believe in a patient-centered approach. We should ensure that products on the market are cleared and consistently perform against the standards they were cleared for. In order to get to that point, we need a robust and fair program. And we need to work with payers.

Dr. Perfetti: Patients obviously deserve to have accurate readings of their blood glucose levels. If a surveillance program is put into place, we need to be sure that it does not cause additional obstacles for patients, and that it is not perceived as a deterrent to using meters. I believe that the problem of not measuring, unfortunately, might be even greater than the problem of inaccurate measurements. 

Mr. Scott: The accuracy requirements are adequate, but we don’t have a system that is holding up to those requirements in the market. DTS’ Post-Market Surveillance Program is the best idea we’ve heard to approach a solution to that program.

Dr. Vigersky: I just want to make a comment on payers, building on the comments of our colleague from Baltimore. We heard from payers a couple days ago, and they said that this issue of accuracy isn’t on their radar screen. They do not understand or appreciate the impact that inaccurate meters might have. One potential outcome of the Surveillance Program is that it gets to payers and makes them aware of the impact of inaccurate meters. This also relates to cost. Yesterday, Claudia Graham showed data that modeled the cost of hypoglycemia. I’ve also modeled the cost in the insured population, including some type 1s and type 2s on insulin. If you look at the hypoglycemic unaware group with a certain known rate of severe hypoglycemic episodes that result in hospitalizations, we’re talking about $15 billion in costs related to hypoglycemia every year. Not all of that is caused by inaccurate meters, of course, but some of it is. Payers need to understand that more accurate meters will reduce costs, not increase their costs.

Dr. Klonoff: I’m hearing a variety of points and opinions from people that are well qualified to discuss this issue. Not everyone agreed on everything, but there were some clear trends. The concepts that I heard were:

• The analytical accuracy of blood glucose monitors is not as great as it should be;
• While we’re trying to improve analytical accuracy, it would also be nice if we could improve some other features, especially adherence and the proper use of information from meters;
• Adverse clinical outcomes occur with analytically inaccurate monitors, at both the low end and the high end;
• Information is helpful to a body like the FDA, and the agency is seeking more information;
• If we want meters to be safe and effective, we have to test to see how safe and effective they are – the more information the better.

There is one area where I don’t think we have clear agreement. If we have a program that accurately tests meters and identifies which meters meet standards and which meters don’t, is that enough to move things forward? Alternatively, would a program like that not be enough, because it is not mandatory, or because it does not come with a promise from FDA in terms of what they would do for any outcome? At the Diabetes Technology Society, we feel that a program that achieves many of our goals would be a good thing. The program we have in mind would not achieve every goal. For example, we cannot compel the FDA to take specific actions based on our results – that’s simply not how the law works in the US. The panel expressed support for some of the goals, but not everyone expressed support for every goal. On the whole, the panel seemed to generally support the overall benefit of the DTS surveillance program, although nobody thought it was perfect. We have lots to think about now, which we will talk about at our next steering committee meeting. We hope we can come up with something that will be beneficial for patients, providers, payers, and the FDA.

Controversies in Developing the Artificial Pancreas

Artificial Pancreas Award

David Klonoff, MD (Mills-Peninsula Health Services, San Mateo, CA)

Dr. David Klonoff presented this year’s artificial pancreas award to Dr. Ed Damiano, highlighting the work of the Bionic Pancreas published in NEJM in June. In DTS tradition, Dr. Damiano had not been notified he was winning the award, and indeed, was surprised upon taking the podium: “That is a surprise. I had no idea. I want to thank you for this honor. I’m really glad I made my flight. Well, in fact, I didn’t make my flight. In my usual way, I missed my flight today, but a nice lady behind the counter put me on another airline for free. So I guess it’s my day!

[Regarding the award,] I think it’s a bit premature. We are not done with this problem. We are well on the way, but we have not delivered a technology to people with type 1 diabetes. We still have a long road ahead of us.” We felt this was a noteworthy award acceptance, given all the press and progress this year – clearly, Dr. Damiano is still laser-focused on the end-game: getting a Bionic Pancreas approved for his son by 2017. 

• Previously, the DTS Artificial Pancreas Award has gone to FDA’s Dr. Steven Gutman and Arleen Pinkos (2009), Dr. Claudio Cobelli (2010), FDA’s Chip Zimliki (2011; now at Medtronic), Drs. Lutz Heinemann and Hans DeVries (2012), and Medtronic’s Drs. Fran Kaufman and John Mastrototaro (2013).

Outpatient Trials Of A Bionic Pancreas In Adults, Adolescents, and Pre-Adolescents

Ed Damiano, PhD (Boston University, MA)

Dr. Ed Damiano presented the latest interim results in seven patients from the ongoing Bionic Pancreas 11-day multi-center study (two additional patients from the five presented at CMHC 2014 in October). Average glucose has been 140 mg/dl (an A1c of ~6.5%) in those on the Bionic Pancreas, with just 0.4% of the time <60 mg/dl and 19% of time >180 mg/dl. The time in hypoglycemia was a particularly notable improvement, as the rate of hypoglycemia <60 mg/dl in prior outpatient Bionic Pancreas studies exceeded 1%. Dr. Damiano is “really thrilled” with these interim results , and noted they have come with no increase in insulin dosing (0.69 units/kg/day on usual care vs. 0.7 units/kg/day on bionic pancreas). Five weeks from now, the team will be halfway done with the ongoing multi-center study, with another 20 patients slated for study at Stanford and UNC Chapel Hill in early 2015. The remainder of Dr. Damiano’s presentation shared prior data and accentuated key debates.

• Dr. Damiano was not present in Q&A to address Dr. Hovorka’s presentation; however, he emphasized that the Bionic Pancreas (BP) did not deliver more insulin than usual care (UC) in three of the team’s four outpatient studies (when there was perfect parity between the control arm and experimental group): 2013 summer camp study [0.79 units/kg/day UC vs. 0.82 units/kg/day BP]; 2014 summer camp study [0.68 units/kg/day UC vs. 0.66 units/kg/day BP]; and multicenter study preliminary data in seven patients [0.69 units/kg/day UC vs. 0.70 units/kg/day BP].
  
  • The one exception was the Beacon Hill study, where the Bionic Pancreas delivered more insulin than in the Usual Care arm. The greater insulin use came in the 11 participants whose mean glucose was >154 mg/dl during usual care, not for the nine participants whose mean glucose was < 154 mg/dl during usual care). In a follow-up conversation, Dr. Damiano shared two reasons why the bionic pancreas may have delivered more insulin in Beacon Hill: (i) the 11 participants that used more insulin on the bionic pancreas than in usual care may have been underinsulinized under usual care, since all 11 of those subjects had glucose levels >154 mg/dl under their own care; and (ii)  different participant behavior on the bionic pancreas (e.g., eating out at restaurants every day vs. usual care eating at home). Indeed, the team has anecdotal evidence that Beacon Hill participants took significant liberties with regard to carbohydrate consumption on the Bionic Pancreas relative to what they did on their own care at home. Even still, insulin utilization in the comparator arm for those subjects who achieved mean glucose levels below 154 mg/dl on their own care were not statistically significantly different from the amount of insulin they received on the bionic pancreas.
• Dr. Damiano did not cover plans beyond the multi-center trial; as of the last update at CMHC 2014, there were several bionic pancreas studies being considered for 2015: a bionic pancreas set point study; an alcohol tolerance clamp study; and an additional pediatric study.
• Dr. Damiano again shared topline results from the 2014 Summer Camp study in pre-adolescents (first shown in October at CMHC 2014), which were very consistent with prior and ongoing results: participants in the bionic pancreas group had an average blood glucose of 137 mg/dl (estimated mean A1c of ~6.4%, with all participants under the ADA goal of 7.5% for teens and pre-teens) and spent significantly less time below 60 mg/dl (1.2%) and above 180 mg/dl (17%) compared to the control condition.
• In line with prior presentations, Dr. Damiano highlighted the bionic pancreas algorithm’s ability to handle a wide variety of insulin doses and patient types. The system gave on average 11 units of insulin per day to one six-year-old female participant who weighed only 47 lbs (21 kg) vs. nearly 15 times as much insulin on average (158 units per day) to a nearly 300-lb (130 kg) subject in a previous study. As a reminder, the algorithm is adaptive and learns continuously over time from its own insulin dosing; it also automatically titrates insulin up or down based on transient insulin resistance, insulin sensitivity, etc.
  
  • We’d note that Dr. Damiano’s algorithm has always had a high degree of adaptability, and it seems like other algorithms are now trending in this direction, per Dr. Claudio Cobelli’s presentation (see below). We think this is a prudent and necessary move, given the high degree of intra/inter day variability in insulin sensitivity.

Controversies in Developing the Artificial Pancreas

Roman Hovorka, PhD (University of Cambridge, Cambridge, UK)

Dr. Roman Hovorka’s comprehensive update on the Cambridge group’s artificial pancreas progress included pooled results from two of the group’s overnight closed-loop studies (Hovorka et al., BMJ 2011, Hovorka et al., Diabetes Care 2014), along with a direct comparison to the Beacon Hill Bionic Pancreas trial (Russell et al., NEJM 2014) and his group’s recently published day-night study (Leelarathna et al., Diabetes Care 2014). On the latter, Dr. Hovorka questioned the additional value of a dual hormone approach. He expressed concern that the Boston researchers are not only overly aggressive in their use of glucagon, but that insulin-only approaches can provide just as good control as using both hormones. We thought his analysis was thought-provoking, though altogether difficult to unpack, given that the trials were different.

• In directly comparing Beacon Hill with his team’s work, Dr. Hovorka suggested that insulin-only systems may provide similar control to insulin+glucagon systems. He did acknowledge that the Bionic Pancreas achieved greater reductions in mean blood glucose from the same baseline of 159 mg/dl (133 vs. 146 mg/dl) and greater time in range of 70-180 mg/dl (80 vs. 73%) than those seen in the Cambridge study; however, he stressed that patients on the Bionic Pancreas also spent slightly more time in hypoglycemia than those on insulin-only closed-loop (4.1% vs. 3.1%).
  
  • Dr. Hovorka also asserted that the comparison to the control group in the Cambridge study was more challenging than in Beacon Hill. First, the Cambridge team used an intention-to-treat analysis (whether closed-loop was functioning or not), while Beacon Hill only considered time when closed loop was operational. Second, the control group in the Cambridge study had real-time CGM always available, while only ~50% of patients in Beacon Hill were on real-time CGM (i.e., patients who did not normally wear a real-time CGM to manage their diabetes were not given one during the usual care arm).
• Dr. Hovorka characterized the Bionic Pancreas’ use of insulin and glucagon as “aggressive.” He noted that in Beacon Hill, participants had a 32% increase in their daily insulin dose during closed-loop. He implied that the increase results from a “stop-and-go” approach to hormone administration that, in his eyes, aggressively doses insulin and depends on glucagon to counteract that “excessive” administration. Dr. Hovorka also pointed to glucagon administration in these patients that exceeded physiological levels (0.8 mg per day). As he stated: “One approach to glucagon is to use it as a brake. The other is stop-and-go. I’ll leave it to you to decide which category these data fall in.”
  
  • While Dr. Hovorka was thought-provoking in his talk, we would note that the studies are difficult to compare. Specifics can vary drastically from study-to-study, which makes it challenging to put the stats up side by side and draw conclusions. In addition, as noted above, the Bionic Pancreas (BP) did not deliver more insulin than usual care (UC) in the other three outpatient studies.
• Dr. Hovorka also pointed out that participants in Beacon Hill had one-on-one nursing. Unlike the Cambridge team’s insulin-only study, participants in Beacon Hill were able to receive “assistance” from nurses to “problem solve” and troubleshoot. In this light, Dr. Hovorka positioned his team’s findings as more “real-world.” He did not offer a definitive conclusion from this data, though emphasized that this was food for thought.
  
  • Notably, FDA’s Dr. Patricia Beaston corrected Dr. Hovorka in Q&A. She emphasized that nurses’ ability to intervene in Beacon Hill was limited, and implied that their presence did not significantly influence results: “I wanted to clarify that the purpose of doing fingersticks and having nurses around for Ed’s study was so that nurses could do troubleshooting or provide guidance. They were there to provide safety monitoring. There were also concerns that the sensors were self-referential and reporting their own success. The fingersticks allowed him to validate the data he was getting from sensors and demonstrate that he was getting an adequate estimation of what the blood glucose was doing.”

Some Answers

Claudio Cobelli, PhD (University of Padova, Padova, Italy)

Dr. Claudio Cobelli discussed the state of the art in algorithm development. Notably, he said that with Dexcom’s new G4AP algorithm (MARD: 9.0%; launched online on Thursday), “the glucose sensor is no longer a gating item” for the artificial pancreas. Dr. Cobelli then reviewed recent tracer work from the Mayo Clinic (Basu et al., JDST 2014) to model glucose transport from the blood to interstitial fluid – he called for more physiological studies on this front. His team is also incorporating the variability in intra/inter-day insulin sensitivity through an adaptive controller – this is a major win for patients, since it is often the day-to-day variability that makes managing type 1 diabetes so challenging. In collaboration with UVA, Dr. Cobelli was excited to note the completion of successful five-night overnight artificial pancreas studies (Brown et al., DT&T 2014; the teams are now moving to two-month bedtime and one-months 24/7 studies.

• With Dexcom’s new G4AP algorithm (MARD: 9.0%; launched online on Thursday), “the glucose sensor is no longer a gating item” for the artificial pancreas. Dr. Cobelli said it should be available in Europe by the end of the year. He praised Dexcom for collaborating with his team to build a better algorithm (using noising and calibration techniques), a great example of an industry-academic partnership – this followed his call three years ago for more such partnerships.
• Dr. Cobelli reviewed recent tracer work from the Mayo Clinic (Basu et al., JDST 2014) to model glucose transport from the blood to interstitial fluid (ISF) – he called for more physiological studies on this front. The goal of this work was to obtain a very finely detailed interstitial glucose time course using microdialysis techniques. The equilibration time between blood and ISF was 8.5 minutes in people without diabetes and 9.2 minutes in people with type 1 diabetes. He emphasized that the delay is time-varied (i.e., a longer time delay at certain points, a shorter time delay at other points). Studies at the Mayo Clinic will examine the time delay during meals and exercise, and he called for further studies in hypoglycemia and insulin resistance.
• Dr. Cobelli highlighted several exciting ongoing outpatient studies through AP@Home and JDRF. The former is studying a total of 36 patients at three centers: two months at home open loop followed by two months at home “hybrid closed-loop” (active from dinner to wake up time; stopped during the day). An additional arm will add one-month at home, 24/7 closed loop. The JDRF-3 trial will examine 30 patients at 6 centers: Stanford, Sansum, UVA, Montpellier, Padova, and Israel. Three weeks at home of open loop will be followed by two weeks at home of hybrid overnight closed loop and then by another two weeks on full day-and night closed loop. This study was recently extended to up to 6 months of closed-loop control at four of these centers.
• Dr. Cobelli’s team is incorporating the variability in intra/inter-day insulin sensitivity through an adaptive controller. The team has identified seven patterns of insulin sensitivity based on time of day, which are incorporated into an adaptive controller that modifies insulin:carb ratio based on time of day. In simulations, the adaptive component has increased time in target and reduced time spent in hypoglycemia.

Controversies in AP Development

Eyal Dassau, PhD (University of California Santa Barbara, Santa Barbara, CA)

Dr. Eyal Dassau provided a remarkable overview of closed-loop technology development to date. His presentation drew from the “Artificial Pancreas database” that the UCSB group has created by curating the past ten years of published clinical trials in the field. We cannot ever recall seeing such a comprehensive review of the various closed-loop approaches. Based on this database, Dr. Dassau was able to share fascinating data on a number of “controversies” within the closed-loop field, such as the popularity of dual-hormonal approaches, the distribution of control algorithms, and the various strategies to deal with meal challenges.

• Dr. Dassau’s findings drew from the “Artificial Pancreas database, ” a novel research tool that acts as a database of artificial pancreas clinical studies. The database contains information on 65 trials, spans 10 years (2004-2014), and was established by searching PubMed and Web of Science with the following keywords: i) Closed-loop diabetes, ii) Artificial pancreas, iii) AP, and iv) Bionic Pancreas.
• Dr. Dassau first shared data on the number of published clinical studies per year over the past decade, stressing that the artificial pancreas field is growing at an “exponential rate.” Though not necessarily surprised, we were impressed nonetheless to see how the field has exploded, considering that there were ~2 published studies in 2004 relative to ~30 studies in 2014.

Table 1: Number of Publications per Year

	2004*	2006*	2008	2009	2010	2011	2012	2013	2014	Total
Number of Publications**	1	3	1	2	7	6	10	11	24	65

*Note that there were zero publications in 2005 or 2007

• The majority of closed-loop studies to date have utilized Model Predictive Control (MPC) algorithms; in fact, the number of studies that have used MPC (32) is nearly double the number that have used all other approaches combined (33). Dr. Dassau was quick to point out that the data does not suggest any single algorithm is the best – rather, each incorporates various features that reflect the priorities and approaches of researchers. As we understand it, algorithm experts are fans of MPC in part because it accounts for delays, a key challenge in closed loop insulin delivery.

Table 2: Number of Algorithmic Approaches

Approach	MPC	PIC	Fuzzy Logic	Other
Publications	32	16	9	8

• A breakdown of meal bolus strategies suggested a roughly equal number of publications using full, partial, and no meal bolus. We’d note that these numbers vary significantly from year-to-year (see below), so it’s hard to say whether the divide is a trend within the field or a statistical anomaly. For algorithm experts, fully closed-loop is clearly the holy grail. However, given the delays in insulin absorption and action, we do not anticipate fully closed-loop would beat hybrid closed-loop for patients eating high carb meals. [The one exception might be fully closed loop augmented by mealtime use of Afrezza.] Of course, there is also a burden tradeoff, which begs the question – by how much does postprandial control suffer with fully closed loop relative to the additional burden brought by hybrid closed loop?

Table 3: Number of Full vs. Partial vs. No Meal Bolus Studies*

	2004	2006	2008	2009	2010	2011	2012	2013	2014	Total
Full	1	0	0	0	0	4	5	5	11	26
Partial	0	0	1	0	2	2	1	2	9	17
None	0	2	1	2	3	0	3	4	5	20

*Only includes studies with meals during closed-loop operation

• Only 17% of closed-loop studies to date (11 publications) have utilized a dual-hormone approach. We know of at least three groups working on dual hormone control – Boston/MGH, Montreal, and Oregon Health and Science University.  
  
  • “I really like glucagon. I see it like the airbag for a car – you like to have it but you don't use it on a daily basis,” said Dr. Dassau. He emphasized that there is a big difference between brakes and an airbag – brakes are used all the time as a control mechanism, while an airbag deploys only in extreme situations as a rescue mechanism. This appeared to build on comments from Dr. Hovorka that the Bionic Pancreas uses glucagon more aggressively than an airbag-like approach. Overall, we see this debate as very important, but challenging to answer at this time until longer, more real-world studies of the Bionic Pancreas are done with a stabilized glucagon and a dual-chambered pump.

Table 4: Number of Unihormonal vs. Bihormonal Studies

	2004	2006	2008	2009	2010	2011	2012	2013	2014	Total
Unihormonal	1	3	1	2	5	6	9	12	28	54
Bihormonal	0	0	0	0	3	1	2	1	4	11

Panel Discussion

Dr. Boris Kovatchev (UVA, Charlottesville, VA): It’s unfortunate that Ed left, because an interesting controversy is whether dual or single hormone control can achieve similar results. We cannot really discuss this without Ed. A similar comparison to the one that Roman presented was done on preliminary data on summer camp studies on children with type 1 diabetes, and found the same result with single vs. dual hormone control, at least in that particular setting. It’s getting interesting in that area, and we will have to see if dual hormone control will be justified, and to what extent. The question is whether glucagon should be a safety mechanism or a control mechanism.

Dr. Jeffrey Joseph (Thomas Jefferson University, Philadelphia, PA): Congrats to all of you. It’s amazing to see the advances that have been made in the past six years. We’ve gone from concept to data to home use. Feasibility and safety have been demonstrated. The technologies we have – sensors, algorithms, pumps – need to be integrated together and made into a usable form. Are these technologies good enough to be a product to help people in the real world? Or do we need a breakthrough, whether it’s better CGM, better pumps, better anything to make it a real product?

Dr. Kovatchev: The technologies are good enough. It’s about system communication.

Dr. Eyal Dassau (UCSB, Santa Barbara, CA): I would agree. The technology and devices are ready. It’s about the performance we would like the system to deliver. And this is just the first generation. The second and third generation will improve performance, lead to better sensors, and insulin will get faster.

Dr. Roman Hovorka (University of Cambridge, Cambridge, UK): In the prototypes, we’ve seen the need for improvement in the human factors element. Patients talk about the importance of reducing size and usability.

Dr. Claudio Cobelli (University of Padova, Padova, Italy): I agree – you can always do better, especially on the insulin side. I don’t think the sensor is the bottleneck. We need the longer studies that are on their way – six-month, 24/7 studies will be a really good test.

Dr. Ali Cinar (Illinois Institute of Technology, Chicago, IL): I would assume that the biggest challenge is to figure out the liability issues. Compared to what people are doing manually, closed loop will do a better job. Early adopters will probably provide good feedback to develop this. People’s expectations will change. They are going to expect narrower bands in glucose variation. That will come through improvements in sensors, algorithms, and insulin. It’s going to be an iterative process to get going from the research side to the commercial side, that’s a burden on industry to see whether it’s feasible.

Q: Is one of the control approaches better than the others in terms of adaptation?

Dr. Roman Hovorka (University of Cambridge, Cambridge, UK): I don’t think we have that information on-site. I think Dr. Damiano’s is probably the most adaptive, because his algorithm starts with body weight alone. I think most other algorithms take into account more factors, such as A1c and insulin daily dose as part of the initial settings.

Dr. Ali Cinar (Illinois Institute of Technology, Chicago, IL): Some of the algorithms are inherently less well suited to adaptability. Some were developed to be fixed algorithms. PID is a typical example. MPC is another one. However, there are techniques that help these algorithms be more adaptive. One can adapt the controller, for example, or one can have a reference model and change things with respect to how the reference model is behaving. However, the latter would not work out for diabetes. In sum, there are certainly some models better suited to be labeled “adaptive” than others.

Ms. Arleen Pinkos (FDA, Silver Spring, MD): In terms of who closed-loop system are most challenging for, is there a correlation between insulin sensitivity levels and performance? If someone is really sensitive to insulin, is it less forgiving to sensor or pump delivery errors?

Dr. Hovorka: We looked at what factors are predictive of closed-loop glucose control. There is a poster here looking at time in target and how it linked to total daily dose, normalized to body weight and baseline A1c. I don’t necessarily remember the results; some are counterintuitive, and some represent way our controller was set up. That is to say, our controller might be different from other controllers. We were lacking in those with higher A1cs in terms of mean glucose values. We need development of controllers to get everyone in the same bracket. We’re also doing studies in people two to six year olds, where we are at the limit of pump delivery accuracy. Manufacturers need to develop diluted insulin for this population.

Q: One of the wonderful things about these devices is their quick learning curve, and how quickly they figure out the optimal insulin pump settings. Is there any consideration of using these devices in the short term to inform insulin pump settings for patients we send home?

Dr. Kovatchev: There are, actually, trials in which people find out that their pump parameters might be off-target after spending time on closed loop control – that happens all the time. I have to warn that the correction factor or carb ratio used by control algorithms for the closed loop do not necessarily apply in the same way to what patients should be using for their own pump therapy, because the distribution of insulin is different with the closed loop.

Dr. Cobelli: I wanted to add that I think insulin sensitivity is very important, especially in the initiation of treatment with the algorithm. We have recently started developing a technique that categorized patients by their carb ratio so that you can start the algorithm with better tuning on insulin sensitivity.

Dr. Patricia Beaston (FDA, Silver Spring, MD): I wanted to clarify that the purpose of doing fingersticks and having nurses around for Ed’s study was so that nurses could do troubleshooting or provide guidance. They were there to provide safety monitoring. There were also concerns that the sensors were self-referential and reporting their own success. The fingersticks allowed him to validate the data he was getting from sensors and demonstrate that he was getting an adequate estimation of what the blood glucose was doing.

Dr. Hovorka: I wasn’t talking about safety issues. I was just saying that our patients were on their own. I think there would be some effect of the nurses being there. I was saying that in order to make a comparison, we need like-to-like studies. I think there’s a chance that the nurses influenced results.

Q: In terms of the change in insulin sensitivity over the course of the day, have you been able to correlate that with activity levels, the amount of fat in the diet, or any other factors?

Dr. Cobelli: I think the issue you raise on insulin sensitivity do need to be addressed. The only study that has investigated the variation of diurnal insulin sensitivity was done in very controlled conditions, abolishing exercise and standardizing diet. These studies need to be done, but this is just the beginning.

New Technology in Continuous Glucose Monitoring

Continuous Glucose Monitoring Technology: Pathway to the Artificial Pancreas

Rebecca Gottlieb, PhD (Medtronic Diabetes, Northridge, CA)

Medtronic’s Dr. Rebecca Gottlieb reviewed the company’s CGM sensor pipeline, highlighting the major goal to build accurate and reliable sensors for the artificial pancreas. Most notable was data on the company’s fourth-generation (Enlite 3) and fifth generation sensors: MARDs of 12% and 8%, respectively in small studies. The addition of intelligent diagnostics (fourth-gen) and redundant sensing (fifth-gen) has clearly improved the accuracy. Dr. Gottlieb also mentioned the EU-launched MiniMed Duo (combo CGM sensor/insulin infusion set) – Medtronic has plans to move to a soft cannula (it launched with a steel cannula), incorporate the latest sensor design/chemistry, and develop a longer infusion set duration to match the sensor. The latter was terrific to hear, since the three-day infusion set wear really hampers the CGM. Last, Dr. Gottlieb mentioned Medtronic’s ambitions in connectivity and software. She did not say “Guardian Mobile” by name (standalone Bluetooth-enabled CGM announced in September), but did highlight a mobile app that will display data, allow access to CareLink, and share text message alerts. We thought it was notable to hear mention of “CareLink analytics,” which sounds like more robust decision support for patients and providers: observations about trends (for patients) and recommendations and insights for behavior modification and device settings (for clinicians).

• Medtronic’s fourth-generation sensor (Enlite 3) has demonstrated an MARD of 12% vs. fingersticks (n=112 sensors; 5,043 paired points). The max daily MARD was 13%. The sensor required an average of 2.3 calibrations per day, and 92% of data was displayed. As a reminder, this sensor adds intelligent diagnostics to measure sensor health. This data was consistent with that shown by Dr. Bruce Buckingham at EASD 2014. Overall, it does mark an improvement over the original Enlite, though it is not as accurate as Dexcom’s G4AP (MARD: 9.0%).
• Medtronic’s 5^th generation sensor demonstrated an MARD of 8% vs. YSI in a small 29-sensor study (n=933 paired points). The maximum daily MARD was 11%, with a higher data display rate (97%) and fewer calibration per day (2.0) than Enlite 3. The fifth generation technology adds a redundant sensor to create the most reliable fused sensor signal. The algorithm weights the output of the more reliable sensor more heavily. Dr. Gottlieb did not specify if this was the orthogonal glucose oxidase/optical sensor – we assume it was not.

Performance of an Updated Real-Time Continuous Glucose Monitor

Jake Leach (VP R&D, Dexcom, San Diego, CA)

Dexcom’s Mr. Jake Leach reviewed the new G4AP algorithm, launched online last Thursday as a G4 Platinum receiver software update – “the first FDA approved CGM to achieve an MARD of less than 10%.” As a reminder, clinical data on this new algorithm was presented in a late-breaking poster at ADA 2014: a MARD of 9.0% vs. YSI in a 51-patient, seven-day study. Mr. Leach presented new clinical data on the G4AP algorithm in pediatrics, which showed that the performance was similar to that in adults. On the company’s 3Q14 call last week, management positioned G4AP as an “important next step on the path to obtaining an insulin dosing claim and the potential of factory calibration.” Mr. Leach did not cover Dexcom’s next-gen pipeline, including Gen 5 (to be submitted to FDA in 1Q15) and Gen 6.

• We’d note that the accuracy improvement between G4 Platinum and G4AP (four percentage points) actually numerically larger than the jump from Dexcom Seven Plus to the G4 Platinum (16% to 13%). Not only did the average MARD improve, but the distribution of sensor accuracy tightened significantly, as the number inaccurate outlier sensors was nearly eliminated. It’s even more notable given that G4AP is simply a new algorithm with denoising and calibration improvements; it uses the same G4 Platinum sensor and receiver. It was built in collaboration with the University of Padova.

New Glucose Sensor Technology

Steve Scott (Abbott Diabetes Care, Alameda, CA)

Abbott’s Mr. Steve Scott discussed the factory calibration, stability, and accuracy of the 14-day sensor used in FreeStyle Libre (he did not call it by name). He did not share any new details on the product, its performance, or its US timeline – the most recent update suggested a pivotal study in the US would begin before the end of the year. As a reminder, the product was launched in Europe in October; see our most recent coverage from Abbott 3Q14 and EASD 2014.

New Sensor Technology: Improved Performance for Higher Reliability

Matthias Axel Schweitzer, MD, MBA (Roche Diagnostics GmbH, Mannheim, Germany)

We were hoping to hear an update on Roche’s novel CGM from Dr. Matthias Axel Schweitzer. Unfortunately, he did not share new data, though it was evident that the company is very invested and enthusiastic about the technology – indeed, he revealed that new clinical data will be shared in the next year as the company looks towards commercializing the sensor. Moving forward, Dr. Schweitzer described plans to conduct in-silico modeling evaluations in order to better characterize the prototype’s clinical accuracy and ability to detect hypoglycemic events (e.g., missed and false detection rates).

• As a reminder, we saw data from the Roche prototype CGM in a poster presented at ADA 2014. The study compared Roche’s CGM to the Dexcom G4 Platinum. The mean seven-day MARD was 10.9% for the G4 Platinum and 8.6% for the Roche prototype.

Sensing Technology: Employing a Direct Electron Transfer Principle

Shinjiro Sekimoto, MS (Arkray Inc., Kyoto, Japan)

New to us, Arkray’s Mr. Shinjiro Sekimoto announced that the company is working to develop a 14-day CGM that employs a novel glucose sensing technology. This “direct electron transfer principle” (DiET) relies on the enzyme glucose dehydrogenase to mediate the faithful and “reliable” detection of glucose. Arkray’s system involves only two components: an on-body sensor (and transmitter) and a smartphone application (see picture below). The sensor is worn on the abdomen and communicates wirelessly with the smartphone. The company has already conducted 14-day in-vitro and seven-day in-vivo studies of the prototype. The latter was conducted in people without diabetes, in which the device demonstrated an impressive mean MARD of 10.9%, ranging from a low of 8.1% to a high of 13.8%. The Clarke Error Grid showed 85% of measurements in Zone A and 15.0% in Zone B (n=849 paired points). However, as there was no mention of sensor performance in the hypo- and hyperglycemic range, we would strongly temper enthusiasm regarding the prototype – it’s not hard to show an excellent MARD when glucose is in range for most of the day. There was also no mention of sensor durability. We acknowledge that preliminary findings are encouraging, but would like to see studies in people with diabetes, along with more details on the sensor’s calibration scheme.      

• Arkray’s system involves two components: an on-body component (sensor + transmitter) worn on the abdomen and a mobile medical app running on a smartphone (see picture below). The app stores glucose readings and provides real-time glucose trend information and, notably, can receive sensor glucose readings wirelessly from the on-body component. The electrode itself measures 0.25 mm in diameter (with an estimated 3 cm length) and is designed to penetrate the skin at an angle (~30 degrees from perpendicular).
• The key element in Arkray’s implantable CGM is the company’s novel sensor chemistry that employs a novel Direct Electron Transfer (DiET) technology. For background, sensing technology involves the reduction of an enzyme via the receipt of an electron from glucose. This electron eventually gets oxidized onto the sensor electrode, which is interpreted to indicate the presence of glucose. Typical sensing technologies have required the presence of an intermediate complex in this process to mediate the transfer of electrons from glucose to the sensor. However, Arkray’s third-generation approach to glucose detection is unique in that it eliminates the need for this intermediary complex by using the enzyme glucose dehydrogenase. This enzyme consists of an FDA-dependent complex that enables the direct transfer of electrons from the enzyme to the sensor electrode. Because of this “direct electron transfer” (from which the technology gets its name), DiET decreases the number of redox reactions required to detect glucose, improves the reliability and sensitivity of glucose sensing, and requires a simpler manufacturing process.
• A seven-day in-vivo study was designed to assess sensor accuracy (MARD) in people without diabetes. Sample size was not provided. Participants were fitted with the on-body component (abdomen) and wore the device for one-week. Sensor performance was assessed via “regular” meal challenges and oral glucose tolerance tests. Unfortunately, device calibration scheme was not shared.
• In the in-vivo study, the sensor demonstrated a mean MARD of 10.9%, ranging from a low of 8.1% to a high of 13.8%. The Clarke Error Grid showed 85% of measurements in Zone A, 15.0% in Zone B, and 0.2% in Zone D (n=849 paired points). There was no mention of the glucose range evaluated, though Mr. Sekimoto acknowledged that there was limited data on the hypoglycemic range in particular. Data on the sensor’s performance in clinically relevant ranges would certainly be useful in ascertaining the real-world promise of the technology.
  
  • Arkray has performed a 14-day in-vitro analysis of the sensor that has demonstrated stability over the two-week period. The key takeaway is that the company is apparently looking to pursue an indication for 14-day-wear. The stability data reminded us of in vitro data on Abbott’s FreeStyle Libre. Though of course, there is long way to go from where Arkray is now to commercialization.
• Moving forward, Mr. Sekimoto highlighted plans to optimize the structure of the glucose dehydrogenase enzyme to enhance accuracy and stability. The company has completed a “protein crystal growth project” that investigated the structure of the enzyme in zero gravity on the International Space Station. This was discussed at a high level. It is unclear whether the findings of the study will translate into clinically relevant changes, though we will stay tuned for more updates on this front.
• This is the first we have heard of Arkray’s interest in the CGM field. In our view, the pursuit is an ambitious one considering Dexcom’s G4 Platinum (MARD: 9% vs. YSI; per the new G4AP algorithm) and Medtronic’s upcoming Enlite 3. Strategically speaking, Arkray has an uphill battle ahead, but certainly there are far too few patients on CGM around the world, and perhaps this new sensor chemistry could help reduce manufacturing costs.

Performance of an Implanted Continuous Glucose Sensor in a Multi-Site Study

Mark Mortellaro, PhD (Senseonics, Inc., Germantown, MD)

Dr. Mark Mortellaro presented 90-day data from Senseonics’ clinical trial of its implantable CGM system (fluorescence-based subcutaneous sensor, body-worn transmitter with Bluetooth connectivity, and a mobile smartphone app). The study, which assessed safety and accuracy over three months of continuous home use, was conducted at three clinic sites (South Africa, Romania, India) in both type 1 and insulin-requiring type 2 patients on MDI. Sensor accuracy was compared to lab reference (hexokinase) at seven in-clinic visits. Overall MARD was a strong 11.4%, measured over a glucose range typically seen in type 1 diabetes (40-400 mg/dl). The Clarke Error Grid showed 87% of points in Zone A and 13% in Zone B (n=3,586 paired CGM-hexokinase points) with consistent accuracy into the hypoglycemic range (MAD 9.8 mg/dl < 70 mg/dl – MARD was not provided in hypoglycemia). There was no degradation in accuracy over time, and 92% (22/24) of sensors successfully reported continuous glucose data over the 90-day period. An EU pivotal trial of the Senseonics system is presently ongoing (Clinical Trials Identifier: NCT02154126) in both type 1 and type 2 patients (n=82).

• As we have detailed previously, the Senseonics CGM system has three main components: a subcutaneous implantable sensor (3 x 15 mm) inserted into the upper arm, a body worn transmitter, and a mobile medical app running on a smartphone. Once the sensor is implanted, the only thing a user deals with is the body worn transmitter and the mobile app. The on-body transmitter powers the sensor through near-field communication and relays sensor glucose information to the smartphone app through a Bluetooth LE link. The transmitter is designed to vibrate when either a hypoglycemic or hyperglycemic threshold level is reach. The transmitter is attached via an armband or replaceable adhesive and measures 1.4 cm x 4 cm x 4 cm (0.55 in x 1.6 in x 1.6 in). It can be taken off at any time and put back on without doing anything on the app. The app provides full access to glycemic levels, allows event logging, and permits cloud communication with care providers.
• This clinical study was designed to assess safety and accuracy of Senseonics’ CGM over 90-days of continuous home use. Sensor accuracy was compared to reference (hexokinase) at in-clinic visits every ~14 days in which venous glucose was measured every 15 minutes. Patients were instructed to wear the body-worn transmitter 24/7, removing the transmitter only during water-based activities (e.g., showering), and to recharge the transmitter daily (~15 minutes). Patients performed two calibrations per day using their home BGM (fingersticks entered into the mobile app). Patients in the study included both type 1 and insulin-requiring type 2 patients on multiple daily injections. Dr. Mortellaro did not break down data between the two groups, though we see it as a positive that Senseonics is exploring this population so early in its path to commercialization.
• Sensory accuracy proved to be strong and stable, with overall MARD vs. reference of 11.4% that did not degrade over time. The Clarke Error Grid showed 87% of points in Zone A and 13% in Zone B (n=3,586 paired CGM-hexokinase points). The sensor’s ability was evaluated over a typical range seen in type 1 diabetes (~40-400 mg/dl). Accuracy remained strong in the hypoglycemic range, where overall MAD was 9.8 mg/d with 91% of measurements within 20 mg/dl of reference (MARD was not provided). In hyperglycemia, MARD was 11.0% with 88% of measurements within 20% of reference values.
  
  • An encouraging 92% of sensors (22/24) lasted the 90-day interval. Dr. Mortellaro noted that one sensor failed on day 55 while the second failed on day 84. Both were the result of sensor self-diagnostics when the signal response dropped below thresholds. It is encouraging to hear that the company has built this into the product.
• The sensor showed strong accuracy for up to 10 hours after a calibration; however, between 10-12 hours post-calibration, MARD began to trend upwards. Dr. Mortellaro noted that this inaccuracy was documented over a low sample size as the study was not originally designed to test more lengthy inter-calibration intervals. Moving forward, the company intends evaluate this parameter more judiciously. The average number of calibrations per day was not specified, though patients were advised to perform two per day.
• The sensor reported 20% missed alarms and 12% false alarms at the hypoglycemic threshold (< 70 mg/dl). Performance in the hyperglycemic range (< 180 mg/dl) was stronger, with only 11% missed alarms and 7% false alarms.
• An EU pivotal trial of the Senseonics system is presently ongoing (Clinical Trials Identifier: NCT02154126) in both type 1 and type 2 patients (n=82). The seven-center study – with locations in Germany, the UK, and the Netherlands – will compare the accuracy of the sensor to YSI at 11 in-clinic visits over 180 days; in-clinic visits will span up to 24 hours, including overnight stays. Patients will prospectively calibrate the system twice a day with fingerstick values. The primary endpoint is that the device’s accuracy (MARD) vs. YSI should be <20%, a fairly low bar for CGM these days, considering the next frontier is 10% and lower. This should be fairly easy for Senseonics to meet, assuming the clinical data holds up. The principal investigator at the Netherlands trial site is the highly regarded Dr. J. Hans DeVries; no other sites are listed on the ClinicalTrials.gov page. Interim 90-day data will be shared at ATTD 2015, and full 180-day data could come at ADA 2015. The study’s estimated primary completion date is this month.
  
  • Senseonics plans to conduct an interim analysis of data at 90 days that will be used to pursue CE Marking. The company still plans to pursue a six-month implantation indication, but will only look to amend this following 90-day approval. We think this is a smart strategy to get the product to market sooner, but leverage the ongoing trials to go for the ultimate 180-day indication.
  • The pivotal study will also use subcutaneous upper arm insertion of the sensor. The company is planning for initial approval at this one on-body site – however, at our last update, we did hear that management intends to pursue alternate locations as well.
• Dr. Mortellaro did not discuss the timeline or pathway for US approval for the sensor. When Senseonics secured $30 million in funding in August, management said that a US pivotal trial would begin in 2015 in approximately 75 patients. If things move as planned, Senseonics could file a PMA with the FDA in late 2015 and launch the product in late 2016. The company has not decided whether it will partner or commercialize on its own in the EU or US.
• Key questions remain answered for Senseonics:
  
  • What fraction of patients would choose the implantable CGM over subcutaneous offerings?
  • What will competition look like in one or two years time (Dexcom Gen 5, Medtronic Enlite 3 and beyond, Abbott FreeStyle Libre)?
  • How will Senseonics’ CGM be priced? Cheaper than subcutaneous options?

Panel Discussion – Selected Q&A

Dr. David Klonoff: I am extremely impressed. I cannot remember a better session at any of the Diabetes Technology Meetings. When we first started discussing CGM, a little over 10 years ago, there were many issues – terrible accuracy, we didn’t have real time data, the sensors would last for three days, the data would drop out, and we had poor stability. We were trying to make something out of this technology. We’ve got great features now: low glucose suspend; real-time data; use of multiple sensors simultaneously to give better average data; algorithms to give the best sensor; excellent accuracy – everybody is now getting down to a MARD of 10%, which was a limit. This bodes very well for CGM to become widely used. And we’re not only seeing excellent accuracy across the board, but also in hypoglycemia. We saw a 14-day sensor, factory calibrated. That’s huge. Now we’re seeing new technology in the early stages using a 3^rd generation enzyme. That’s so important and looks promising. We saw 90-day implanted sensor data that looked great. It’s early, but anything that last 90 days is promising. Over the years, one of meeting co-sponsors has been NASA. You may have asked, “What the heck is NASA doing here?” Now you know.

Q: On the implanted subcutaneous sensor, were there any adverse reactions to site? Were there differences in insertion sites?

Dr. Mortellaro: We only did forearm insertions. We have done insertions in the abdomen, and there is some promising data there. No, there were no site reactions reported on the device.

Dr. John Pickup: We’ve seen variation in MARD. The mean is often good. But sometimes you get a MARD of 20%. Presumably you cannot predict that. What is going on with the outliers?

Dr. Matthias Axel Schweitzer (Roche Diabetes Care, Mannheim, Germany): It depends how you understand the question. Are there outliers? Yes of course. It also depends on physiology. We can use two or more parallel sensor to figure out the physiological impact. The architecture of using different spots for the working electrodes makes the sensor much more robust and reliable, and significantly reduces outliers.

Mr. Jake Leach (Dexcom, San Diego, CA): By far, the biggest driver of outliers is inaccurate calibration. That’s what we tackled. We’re not always treating a fingerstick value as a gold value. There is some error in that, and we account for that.

Q: To Senseonics, how do you recognize a failure of the sensor vs. a complete dropout?

Dr. Mortellaro: It’s about signal strength and current. We’ve set thresholds, and a failure means it has fallen below those thresholds.

Dr. Pickup: For the DiET system, you mentioned oxygen insensitivity. What is the factor responsible for the stability? Second-gen sensors were meant to be oxygen insensitive. Yet they suffered from a lot of drift. What is responsible for the good performance? What is it that you’re doing for these new fantastic results?

Mr. Shinjiro Sekimoto (Arkray, Kyoto, Japan): I’m not sure. Luck of experiment.

Mr. Steve Scott (Abbott Diabetes Care, Alameda, CA): Sensitivity to peroxide itself has an effect on the enzyme.

Dr. Pickup: For the people in fluorescence, tell us about photobleaching. Is that a big problem?

Dr. Rebecca Gottlieb (Medtronic Diabetes, Northridge, CA): I don’t have information on that.

Dr. Mortellaro: The LED is only on for 4 milliseconds per measurements. Pure photobleaching is not the primary means of sensor degradation.

Dr. John Pickup: A question on interference. I’m surprised at how much acetaminophen affects old type sensors. To what extent do these new algorithms and smart sensor features decrease interference.

Dr. Gottlieb: It depends on the potential you drive the sensor at. There are ways to modulate that. Diagnostics can tell you what going on at the time, and membranes will limit the transfer of acetaminophen to the electrode surface.

Mr. Leach: The Seven Plus, our previous gen, was fairly susceptible to acetaminophen. It resulted in a large glucose signal. With the G4 membrane, less acetaminophen gets down to the electrodes. It’s a small response but not nearly as big as the Seven Plus. In the future, we’re working on membranes that actually block acetaminophen completely, so it doesn’t get to the electrode.

Mr. Scott: It’s runs below the level that acetaminophen would have an impact, so there is no interference.

Novel Treatments & New Technology for Insulin Delivery

Insulin Pump therapy in Type 2 Diabetes

Bruce Bode, MD (Atlanta Diabetes Associates, Atlanta, GA)

Dr. Bruce Bode spent much of his talk discussing Medtronic’s Op2tmise trial, published in the Lancet in July (RCT of pumps vs. MDI in type 2 diabetes). He was very positive on the trial results: “Clearly, for pump therapy in type 2 diabetes based on Opt2mise, if you’re failing MDI, you’ll do better on a pump, with less insulin, a significant drop in A1c, and no increase in weight or hypoglycemia.” As he has in the past, Dr. Bode distinguished Opt2mise from the two other large RCTs of pumps in type 2 diabetes (Herman et al., Diabetes Care 2005; Raskin et al., Diabetes Care 2003), as Opt2mise enrolled patients failing MDI (A1c >8%) and on high insulin doses (>0.7 units/kg). In Q&A, Dr. Bode estimated that there are ~100,000-150,000 type 2 pumpers in the US, which has grown dramatically from ~35,000 six-to-eight  years ago (and his estimate of 50,000-100,000 at CDTM 2012). Notably, he has heard that ~30% of pumps now sold in the US are for type 2s. Dr. Bode did not address simple patch pumps (Valeritas, CeQur, etc.), but did note the lack of a randomized trial of such devices. In smaller trials, he said, simple type 2 insulin delivery devices have shown similar benefits to Opt2mise: a decline in A1c, less insulin, and less hypoglycemia.

• Dr. Bode highlighted the key product attributes and potential benefits of pumps in type 2 diabetes.
  
  • Key attributes: effective, simple, discrete, cost-effective, and low risk of hypoglycemia.
  • Potential benefits: improved glycemic control, breaks glucotoxicity, beta cell preservation (shown in some type 1 studies, not sure if this is true in type 2), enhanced quality of life, improved patient satisfaction (“very clear” in studies), and ease of management.
• Dr. Bode highlighted results from Medtronic’s OpT2mise trial, published in The Lancet on July 3 (Reznik et al., 2014). The randomized, six-month study compared insulin pump therapy (n=168) to MDI (n=163) in type 2 patients in poor control (mean A1c: 9.0%). After 27 weeks, A1c declined by 1.1% in those on an insulin pump compared to 0.4% in the MDI group (p<0.001); notably, 55% of the pump group achieved an A1c <8% vs. 28% of the MDI group. Masked CGM data (iPro2; baseline vs. six months) revealed no significant increase in hypoglycemia and significantly greater reductions in time spent >180 mg/dl in the pump group (-226 minutes per day vs. -57 minutes per day; p<0.001). In addition, the group on pumps used 20% less insulin vs. those on MDI at the end of six months (122 vs. 97 units; p<0.001), a major positive for cost-effectiveness and weight.
  
  • Dr. Bode emphasized three sub-group findings: Those with the highest A1c had the strongest improvement; those who bolused more often did better; and those who liked the pump more (via satisfaction surveys) experienced better results.
  • We’d note that Opt2mise is the largest comparative study ever done examining pumps vs. MDI in type 2 diabetes, and it overcame some of the limitations of previous data (e.g., non-randomized, non-poorly controlled patients, small n’s). One could argue that a 1.1% reduction in A1c is fairly small given the high baseline, but we emphasize that this is a highly challenging patient group – late stage type 2s failing MDI. It was quite significant that nearly double the number of patients got to an A1c <8% using a pump, while simultaneously using 20% less insulin and not experiencing any additional hypoglycemia or weight gain. We expect the real-world results in a poorly controlled population would be even better, since control group patients of course received a lot of attention, dose titration, and education.
• Dr. Bode highlighted the importance of patient preference, a key finding from Raskin et al., Diabetes Care 2003. The trial compared pumps vs. MDI in type 2, with no ultimate difference in A1c. However, 93% of participants preferred the pump. Said Dr. Bode, “From a preference and hassle standpoint, as well as feasibility and convenience, pumps won. It was very, very clear, even though there was no difference in A1c.”

Questions and Answers

Q: The data is there that pumps in type 2 work. But the market penetration is incredibly low. Is the technology too advanced? Is the future simpler patch pumps?

Dr. Bode: The type 2 pumps in Europe are slow because of cost/reimbursement issues. When you apply for a pump in the US, you say you’re failing MDI – you don’t say whether you are type 1 or type. 2. It has been suggested that ~30% of pumps sold in the US are for type 2s now. Patch pumps like Insulet are small volume, and for type 1s. But there are growing type 2s on the pump. It’s in the range of 100,000-150,000 patients. It has grown dramatically from 35,000 six-to-eight  years ago.

Q: Opt2mise will hopefully change the view of payers. In Spain, some of my high insulin resistance patients are doing well on pumps.

Dr. Bode: I completely agree with you. If it’s cost-effective, payers will pay for it. Opt2mise used no other drugs besides metformin. So you get rid of other drugs, especially branded drugs. There is a pilot ongoing in the US with Aetna; we are looking at high insulin users that are poorly controlled.

Q: I appreciate what was demonstrated in Opt2mise. There is some controversy in the type 2 population. I’m at Veteran’s hospital in Cleveland. Our experience in type 2 pumps is that they are often not screened for being tech-savvy. We see issues with engagement – patients not bolusing at mealtime. They think it’s like a George Foreman oven: set it and forget it. So they don’t get to target, but have these expensive supplies. We do need to scrutinize who we are prescribing pumps for. My question is about using U500 in pumps in extremely obese patients. We use it as a basal insulin, and can often bolus with it.

Dr. Bode: U500 is a very stable pump insulin. But it’s a terrible bolus insulin. It’s like giving NPH for bolus insulin. Insulet is doing an FDA study to get U500 approved for its patch pump. To bolus with U500, it lasts 12-14 hours. You have to cut the basals down. You have to use rapid-acting insulin to cover meals.

Dr. David Klonoff: I enjoyed your presentation. What do you think about combining an ultra-rapid-acting insulin like Afrezza? Maybe then you get the best of both worlds?

Dr. Bode: I completely agree. Al Mann, has a miniaturized pump that can take U500. Afrezza with a good basal would be very easy and simple. It’s relatively discreet, and people don’t have any trouble inhaling in public. I think it is an option. We also need concentrated faster acting insulins we need as well.

Is Diabetes Technology Better in the US or Europe?

Is Diabetes Technology Better in the U.S. or Europe?

J. Hans DeVries, MD (Academic Medical Center, Amsterdam, Netherlands)

Dr. Hans DeVries gave a humorous presentation to open the debate, addressing the topic from several angles: financial effort; diabetes technology meetings; journals; companies; recent high impact papers; regulatory climate; research environment; and reimbursement. His talk was balanced and gave both sides the edge on different factors, leading to a comical conclusion, “Diabetes technology is perhaps slightly better or worse in the US, but many other things are better in the EU.”

• Diabetes Technology meetings (Winner – US): Dr. DeVries cited DTM and ATTD as the best meetings, ADA in the middle of the slide, and EASD at the bottom (“the attention of EASD to diabetes technology is insufficient”). An example of EASD’s inattention to the field is “best illustrated” in Medtronic’s Opt2mise trial – the paper made it into the Lancet but didn’t get further than a poster at EASD 2014. Dr. DeVries said that some researchers in the field have recently chosen not to submit their data to EASD.
• Journals (Winner – US): Dr. DeVries gave the Journal of Diabetes Science and Technology the most praise for its focus on the field; Diabetes Technology and Therapeutics follows closely with a small fraction of papers dedicated to non-technology topics. He noted that Diabetes Care seems to be more restrictive in accepting technology papers now that JDST and DT&T have established themselves. “What is clearly missing from this list,” he said, “is any European journal.”
• Companies (Winner – US): Dr. Devries focused on CGM – “Perhaps the most important advance of the last 10-15 years” – and the three US-based companies (Medtronic, Dexcom, Abbott).
• Recent high impact papers (Tie): Dr. DeVries briefly mentioned the two recent closed-loop papers that appeared in NEJM (Russell et al., 2014; Philip et al., 2013), one from the BU/MGH group and one from the DREAM consortium in Israel. He noted the publication of ASPIRE in NEJM (Bergenstal et al., 2013), but noted that Dr. Thomas Danne published very similar results in DT&T in 2011.
• Regulatory climate (Winner – Europe). Dr. DeVries acknowledged that the US and Europe have completely different procedures, but several examples point to a European victory: (i) market access to the Medtronic Veo was delayed for four years in the US; (ii) Abbott’s FreeStyle Navigator, the best CGM for years, was only very briefly available on the US market; (iii) insulin degludec, now on the EU market, is not available in the US and is awaiting a cardiovascular outcomes trial. Dr. DeVries was particularly perplexed on the need for CVOT for an insulin.
• Research environment (Winner – Europe): Senseonics, Glumetrics, and Echo Therapeutics went to Europe to do their preliminary research, “directly related to the regulatory climate.”
• Reimbursement (Tie): Dr. DeVries noted improving CGM reimbursement in Europe, with coverage in Belgium, the Czech republic, and many other countries online. Notably, German reimbursement approval for CGM will “probably” come through in the next few months. He said that CGM reimbursement is good in the US when people are insured, though the lack of Medicare coverage is a major negative.
• Financial effort: Dr. DeVries showed a graph plotting healthcare system ranking with national spending. The US was ranked #11, while Sweden is ranked #2 (at half of the price). He concluded that financial effort is “not a useful yardstick,” since there is no clear relationship between the amount of money spent and quality.

Diabetes Technology: US vs. Europe

Barry Ginsberg, MD, PhD (Diabetes Technology Consultants, Wyckoff, NJ)

Dr. Barry Ginsberg took a wholly entertaining approach to assessing technological progress in the US and Europe by highlighting each nation’s contribution to innovation in diabetes. Using an amusing scoring system, Dr. Ginsberg assigned points to each nation for the novel “life-changing” technologies each had brought to the diabetes community in several categories (pumps, CGM, BGM, pens, syringes). Dr. Ginsberg teasingly concluded that the US – based upon his scoring system (below) – has contributed the lion’s share to innovation in diabetes technology.  

• Insulin pumps (TIE): Dr. Ginsberg traced insulin pump innovation to work in both the US and Europe. As expected, he highlighted the work of Mr. Dean Kamen from the US, who developed what is widely considered to be the first portable insulin infusion pump in 1973. However, Dr. Ginsberg also credited the National Institute for Medical Research (London, UK) for the Mill Hill Infuser (1976) in Europe.
• CGM (Winner – US): Dr. Ginsberg credited Medtronic (2003) for the most significant innovation that the field of CGM has seen. He did acknowledge that GlucoWatch was commercialized before Medtronic, though suggested that the penetration of the latter has much more significantly “changed people’s lives.”
• BGM Accuracy (Winner – Europe): According to Dr. Ginsberg, Roche was responsible for the “single biggest jump in accuracy” seen in the BGM industry when the company commercialized the Accu-Chek Advantage.
• BGM Communication/Data (Winner – US): Dr. Ginsberg acknowledged that Bayer has done a lot to improve BGM interfacing and data presentation. However, he ultimately credited the US company, AgaMatrix, for moving data onto the iPhone. Indeed, we would agree that the move to smartphone/cloud-connected meters has revolutionized the way patients and providers can access data and, unsurprisingly, this industry is in the midst of rapid expansion. For an overview of the smartphone/cloud-connected industry, see our landscape overview here.
• BGM Sensor (Winner – US): The ExacTech was credited with sensor innovation for the development of the Companion in 1991.
• Insulin pens (Winner – Europe): Novo Nordisk earned points for Europe in this category for introducing the diabetes world to the insulin pen in 1985.
• Insulin Syringe (Winner – US): The development of plastic insulin syringes (BD, 1963) changed the nature of insulin administration. Rather than boiling glass syringes, Dr. Ginsberg highlighted that utility of disposable plastics.

Table 1: Final Scoring Tally – US vs. EU Innovation

	US	Europe
Insulin pump	75 points	70 points
CGM	50
BGM Accuracy		35
BGM Communication/Data	45
BGM Sensor	55
Insulin Pen		70
Insulin Syringes	70
Total	295	175

Panel Discussion

Q: I think we should also remember that more than 80% of the enzymes for diagnostic use in glucose sensing are from Japan. Many of the developments in BGM have come from Japan as well. Many high quality sensors come from Japan, and also Korea. I would appreciate it if you can remember the contributions from the large Asian communities in the field of diabetes technology.

[Applause]

Dr. Timothy Bailey (AMCR Institute, Escondido, CA): Does anyone want to bring up any other underreported geographic areas?

Dr. John Pickup (King’s College, London, UK): Can you talk about the role of technology assessment? What is the roles of organizations like NICE and IQWIG? Do you think that the role they have in evidence-based assessment and deriving guidelines are matched by US organizations?

Dr. Barry Ginsberg (Diabetes Technology Consultants, Wyckoff, NJ): I don’t qualify as an expert, but I think they are not. The agency for quality healthcare does some of this in the US. I’m not sure how well they do it. The other part of it is that the payers tend to be more easily influenced in the US by political considerations.

Dr. David Kerr (Sansum Diabetes Center, Santa Barbara, CA): Having been involved in NICE, it is a worthwhile approach. I was involved in the insulin pump piece. It’s good to hear that the voice of the person with diabetes is heard by NICE. It’s an evidence-based approach, but they are taking guidance from people with diabetes about what was said.

Q: If you look at those numbers, since they are all cross-sectional, you’re looking at two things within an age group: patients who started using pumps within that age group and patients who started earlier and have carried over into their present age group. Especially in Germany and Austria, where there were higher use numbers at ages under 6, does that mean patients are discontinuing pump use later on or something else?

Dr. David Maahs (University of Colorado, Denver, CO): I think that’s really striking. I’m not sure if they’ve changed their practice policy in the past few years or so and are starting more children on pumps. I don’t know whether those kids will carry forward and increase numbers in higher age groups as time goes on. We do need a longitudinal assessment of that. I think one of the reasons that these registry and database analyses are useful is to point out what we’re doing better or worse. We had an analysis of children under six-years-old published in Diabetologia and we found that, in the US, A1c numbers are quite a bit higher. In the US, we need to do better job managing diabetes in children. Perhaps the problem is the way we are handling pumps. Or perhaps it’s CGM. But we really can learn from how the US is doing.

Q: One question has been, how many patients discontinue pump therapy overall. Was that data gathered?

Dr. Maahs: Yes, it was gathered. I believe we’re in the process of looking at that data, but don’t have it yet. But I agree, it’s very interesting to look at.

Dr. Pickup: Could we talk about the acquisition attitudes towards technology in Europe, particularly with regard to pump uptake? It’s always been the suggestion that the lower UK pump uptake is because the physician body is not committed to the notion of technology, and that goes beyond diabetes. Is the attitude better in the US?

Dr. David Kerr: I think the really disgraceful pump penetration in the UK is due in part to doctors. For some bizarre genetic reason, physicians in the UK don’t like shiny things. In the US, it’s the opposite: if you give an American a shiny thing, it’s just … passion. I suspect there is an in-between place that is a better place to be. Having worked in Silicon Valley, it’s astonishing what’s being created, but it’s a question whether or not people will actually use them.

Dr. David Maahs: The data we have on lower pump use in the UK, as well as data suggesting better A1cs with pump use, should help people in the UK advocate to address the trend.

Dr. Hans DeVries (Academic Medical Center, Amsterdam, Netherlands): I would point out that a pump is a tool that people can use if they benefit from it. In my opinion, pump discontinuation is not by definition a bad thing. If the tool isn’t helping the patient anymore – perhaps if a patient started at age five and is now 15 and has other priorities – there is no reason not to discontinue. We have to be cautious about the A1c comparisons between MDI and pumps: these are different types of patients. It’s just about what suits the patient best.

Dr. Ginsberg: I think the US is heterogeneous in the use of technology across the country. I think there’s much less use of technology in the Midwest. I have seen that cities in this region make decision on whether to use drugs based on the five-year review of the product. So, the east and west coasts tend to be more involved in technology than the Midwest.

Mr. Adam Brown (The diaTribe Foundation, San Francisco, CA): There seems to be a disconnect between the trials needed for clinical effectiveness and reimbursement in the Europe and US. Should we be connecting those two or thinking more deliberately about this?

Dr. DeVries: Of course you are completely right. The difficulty, as always, is having to please both of those bodies.

Dr. Ginsberg: At least with the companies I deal with, they want to keep these separate. The kinds of outcomes you are looking for in reimbursement trials are different from the outcomes you are looking for in regulatory trials. You want to focus carefully on your goals.

Dr. Bailey: You had great cross-sectional data on pump usage. Do you have any data on CGM?

Dr. Maahs: Denise Wong at UCSF published some data from the T1D Exchange last month in Diabetes Care looking at CGM usage. It’s somewhere around 10%. The problem was that this data was fairly old, but in the Exchange, we still see fairly low penetration of that technology.

Dr. Bailey: Is there data from European registries about CGM?

Dr. Maahs: We look at it in the under six-year-old group in the Exchange vs. DPV, CGM penetration was about 6% in both registries. We do have an analysis of the DPV in patients over six years old. It will be presented at Endocrine Society, and is fairly similar.

Ms. Arleen Pinkos (FDA, Silver Spring, MD): I’m from the FDA – do we have any information on what areas do a better job of educating diabetic patients?

Dr. Kerr: I can tell you that from the UK national audit of diabetes, I believe the figure for the proportion of type 1 diabetes patients who have attended a structured education program is at around 2%, so quite low.

Dr. Maahs: As far as the ratio of patients to providers, I have the impression from speaking to people at ISPAD that in Europe there is a lower ratio of patients to providers than in the US, and that in general there are more resources.

Dr. Pickup: It might be true that more patients have structured education in Europe than in the US. In the UK it’s very difficult to get onto a pump unless you’ve had structured education, and I’m not sure if that is the case in the US.

Dr. DeVries: In Germany we see a lot of emphasis on education. Generally speaking I don’t think it’s as structured in the rest of Europe, but there really is a lot of emphasis on it. I think many European pump users have done the equivalent of structured education.

Dr. Maahs: We have a very structured program at the Barbara Davis Center, with multiple classes. They differ across the USA. I think that with CGM, we’re learning how to get the product to patients. It’s a new technology, and it will be different again if we move to integrated systems.

Mr. Adam Brown: We’ve heard that CGM penetration is low in the US and Europe. Do you think CGM will eventually outstrip pump penetration? And if it accelerates, what will be the game-changer? Will it be CGM going to phones? Will it be factory calibration?

Dr. DeVries: Well, if you look at the Dexcom stock price, it’s only going up. This is an indicator that in the future, more people will be embracing CGM. The thing I’m still wondering about is that if you consider the natural extension to the artificial pancreas, then we need to start thinking about developing educational and support materials now in target populations. If you develop this product for everyone with type 1 diabetes, you’ll be disappointed. You need to focus on subgroups and target the product to those who will find it acceptable.

Dr. Ginsberg: I think three things are holding CGM back: accuracy, cost, and overwhelming data that people don’t know how to handle. The cost has not changed, though the accuracy has. CGM is now as accurate as BGM was in the DCCT. However, the issue of overwhelming data remains. As these issues continue to get solved, CGM use is going to increase.

Dr. Kerr: A couple other issues I’ve heard relate to comfort, which has gotten much better, and accuracy and alarms. On the latter, a lot of adolescents simply get annoyed whether the CGM is accurate or not.

Dr. DeVries: If you look at the recently launched FreeStyle Libre in Europe, it’s kind of like a disguised CGM. In my opinion, it’s a CGM. The price in Europe is less than 50% of the price of CGM, but the underlying technology is the same. The duration of use is also longer. So I think the price is coming down. And as there is a switch from manual to factory calibration, that will help.

Dr. Pickup: Europe is quite good at innovation, but very poor at turning that into products and exploiting it. There is a tremendous difference in investment – there is six times as much investment in startup companies in the US. How can we improve that in Europe?

Dr. Ginsberg: I don’t know enough about Europe.

Dr. DeVries. There is a European program to do more startups and create more jobs. It’s an easy question to ask and a difficult one to answer.

Dr. Pickup: But what is the reason why?

Dr. DeVries: I wouldn’t come much better than to say the willingness of people in the US to take risks and go bankrupt once or twice in their lives is much higher.

Dr. Ricard Bellazi (University of Pavia, Italy): In Italy, starting a company is expensive. The minimum investment is a thousand dollars just for having your brand name. Even without doing anything. Taxation is very high too. There are barriers related to regulations that make it very difficult to try and innovate. Some people get a degree in an EU university, come to the US, and create a startup here, and then do software programming in Italy. It’s an important issue.

Q: Since discontinuation with pumps can have an impact on outcomes, could we develop a program for pump use like we have for driving, where patients would need to check in every few years?

Dr. DeVries: I think you touched upon an important topic: how can we keep benefitting the most from technology? We all know that there is a tendency with pump users to lose the A1c benefit they gained when they went on the pump. I don’t know about an idea that would involve a re-examination every two or three years.

The Role of mHealth in Managing Diabetes

Mobile Technology, “Making” Health, and the Future of Diabetes Technology

Joyce Lee, MD, MPH (University of Michigan, Ann Arbor, MI)

“The promise of mobile health has yet to be realized,” said Dr. Joyce Lee in opening her talk. In light of a growing younger generation whose lives are contained in devices, Dr. Lee emphasized that the penetration of mHealth is undermined by apps of uncertain quality, uncertain benefit, the lack of a link to a provider, and lack of information on security. These issues are caused by a common problem in her view: the absence of a patient-centered approach to systems design. She stressed that no stakeholder is better suited to drive healthcare changes than patients. Not only are they motivated and willing to solve problems at the pace they need to be done, but they have the experience to identify and inform efficient and effective solutions. This was the impetus, as Dr. Lee described it, for the NightScout/CGM in the Cloud Facebook group, a crowdsourced movement that has “hacked” the Dexcom G4 Platinum receiver to send data up to the cloud and to other display devices. This grassroots action was enabled by patients acting as “expert, maker, and collaborator” that saw an opportunity for the better use of technology and that regulatory processes were not moving fast enough. For more background on NightScout, Dr. Lee introduced NightScout users John Costik, Adrien de Croy, and Weston Nordgren.  

• For more on NightScout/CGM in the Cloud, please see Kerri Sparling’s review in diaTribe, our Closer Look coverage from a few weeks ago and at ADA 2014, and the recent article in the Wall Street Journal.

NightScout

John Costik, Adrien de Croy, and Weston Nordgren (NightScout Foundation, TX)

John Costik, Adrien de Croy, and Weston Nordgren took turns describing how NightScout has profoundly changed the lives of patients with diabetes and their families. It was an emotional and tear-filled session as all three speakers – fathers of children with diabetes – detailed the desperate need that inspired this grassroots action: the ceaseless fear of hypoglycemia, the anxieties of putting their child’s lives in the hands of caregivers at school, and the bureaucracy that has slowed what should be relatively straightforward innovation. They were impressively persuasive, describing access to remote ambulatory CGM data as an absolute necessity with an immeasurable capacity to improve quality of life for both parents (more sleep, peace of mind) and children (more day-to-day normalcy). The discussion certainly struck a chord with attendees – who gave the speakers the longest round of applause on the day. We, too, agree in the power of patients, but have also realized that companies are getting the message loud and clear. Dexcom and Medtronic, in particular, are working to make CGM more connected (see below). Along these lines, we were particularly pleased to hear the speakers embrace the recently approved Dexcom Share as a valuable addition to the “buffet of technologies we use to provide children with the best lives possible.”

• Below, we bring to readers some of the quotes that we thought were most powerful from the emotional session:
  
  • “We wanted our lives back. Wanted what type 1 was taking from us. There’s now this very distinct impact on our quality of life … It’s almost indescribable.”
  • “Everyone got together because of the same common denominator: We wanted a piece of peace back in our lives.”
  • “It has been a great, great blessing in the lives of families … Every parent coming into this had lost a piece of their lives, of what they used to take for granted.”
• We were glad to hear speakers acknowledge that Nightscout and Dexcom Share have the same goal – sharing CGM data with loved ones (especially parents of type 1 children) mainly to increase safety. Ultimately, we are fans of more options for patients, since not every tool appeals to every single patient or family. Broadly speaking, Share is much easier to set up than Nightscout, but also is more limited in functionality and portability. However, we think the points of difference are far less important than the overall message both approaches bring to the diabetes community: new solutions to help patients and caregivers monitor glucose levels with more peace of mind

FDA’s Role in mHealth and Diabetes Management

Beth Stephen, PhD (FDA, Silver Spring, MD)

Dr. Beth Stephen discussed the Agency’s role in supporting mobile health. It was positive to hear her characterization of mobile technology as the key to future diabetes management, especially her acknowledgement that the FDA has a significant role to play in this field. She shared concern that current mobile platforms bring security concerns and difficulties in integrating Apple and Android operating systems – these seem to be clear areas of focus for the Agency Dr. Stephen described on a high level the Agency’s “close work” with industry to establish standards for market entry and upgrades, though it was unclear exactly what such discussions entail. Our impression continues to be that the FDA’s efforts are ongoing, though cannot possibly keep up with the speed of innovation. That said, it’s clear that this is uncharted territory for all stakeholders in this field (industry, FDA, patients, caregivers) and that the FDA’s effort to discuss the challenges and works towards solutions is a big win. Moving forward, Dr. Stephen said that “diabetes-related interoperability is a high priority” for the Agency, something we would wholeheartedly agree with – indeed, key opinion leaders have suggested that communication is the biggest barrier to closing the loop. The Agency plans to publish a general draft guidance on interoperability in the near future (timeline unclear) and though it is not diabetes specific, we see the move as a significant step in a positive direction. It will be most valuable to hear a whole morning session on this topic at Wednesday’s Public Workshop: “Regulatory Science Considerations for Software Used in Diabetes Management.”

• To its credit, the Agency has taken strides toward facilitating mobile health solutions by defining the kinds of medical app devices it will regulate. It has released both its Mobile Medical App Guidance (September 2013) and Medical Data Device System Draft Guidance (June 2014).
  
  • Mobile Medical App Guidance – This guidance outlines the Agency’s tailored approach to mobile apps by defining what products will be regulated by the FDA: (1) apps that are used as an accessory to an already regulated medical device (e.g., a secondary display for a CGM); and (2) apps that transform a mobile platform into a medical device (e.g., a glucose meter that plus into a smartphone).
  • Medical Data Device System Draft Guidance – This document updated the FDA’s regulatory stance on “medical data device systems” (MDDS) that, as of February 2011, were regulated as Class I (low risk). This guidance was issued to inform manufacturers that the Agency would no longer actively regulate MDDS. This document also lays out the distinction between MDDS, which simply aggregate information, and more complex platforms that manipulate data or use data to inform medical decision-making. It defines an MDDS as “hardware or software products that transfer, store, convert formats, and display medical data” that cannot modify data or control the functions of a connected medical device; additionally, MDDS should not be used in conjunction with active patient monitoring.
• “Diabetes-related interoperability is a high priority,” said Dr. Stephen. She stressed that the FDA recognizes the utility of integrating CGM, BGM, and insulin pump data and, notably, is taking action on this front – the Agency is holding a public meeting on November 13 to discuss this topic as it relates to diabetes in particular. There are certainly implications here for the artificial pancreas, as well as for device connectivity with smartphones/apps, and we imagine this will come up several times in discussion. The meeting is a great signal of FDA interest on this front.
• The focus on diabetes-related interoperability is part of a broader FDA campaign centered on communication between devices and systems – Dr. Stephen revealed that the Agency plans to issue a draft guidance on interoperability (not diabetes specific) that will address standards for device-to-device communication and cybersecurity. We would note that the latter is of particular concern in this field. Recently, IBM CEO Ms. Ginni Rometty (IBM, Armonk, NY) shared her belief that the future of mobile healthcare will “hang in the balance of privacy and security.” Considering that 40% of medical data breaches involve some sort of mobile interface, it’s hard to disagree.

User Experience and Behavior Change in mHealth Interventions: Human Factors Engineering

Joe Cafazzo, MD, MPH (Centre for Global eHealth Innovation, University of Toronto, Canada)

Dr. Joe Cafazzo gave a tremendous presentation on the critical importance of “empathy in design,” noting that he doesn’t see much of it health technology. Citing numerous human factors blunders over the years (Chernobyl and Three Mile Island; Al Gore vs. George Bush; medication bottle labels), Dr. Cafazzo made it clear that human factors matter! He focused his presentation on an app called bant, which uses gamification and rewards to encourage adolescents to improve their type 1 diabetes management. Users earn experience points to level up and eventually redeem for iTunes giftcards. In a pilot trial, type 1 patients tested ~50% more frequently with the system. A new and more sophisticated version of Bant is now in a randomized controlled trial – the update adds a social media stream (“banter”), pattern recognition, points leaderboards, and more. Bant for type 2 diabetes is also in development, which places a greater emphasis on paired testing and eating/activity. Dr. Cafazzo emphasized how much thought and polish has gone into the apps, which must compete for time on the smartphone next to Facebook, Google, and Angry Birds: “What app do you want to tap on right now. It’s really important that your apps are as sticky and compelling as some of the apps on your phone.”

Big Data for Diabetes Management

We No Longer Live in the 1990’s: Social Media is Diabetes Technology

Joyce Lee, MD, MPH (University of Michigan, Ann Arbor, MI)

Dr. Joyce Lee gave a truly outstanding talk on the value of social media in diabetes, especially for the clinicians in the audience. Primarily through the lens of twitter, she made a persuasive case that social media IS diabetes technology – it is disseminating tools (e.g., Nightscout, DIY Artificial Pancreas), helping patients troubleshoot, providing patient input to product design, facilitating conversation (#DSMA), sharing useful information, facilitating advocacy (#DOCAsksFDA), and even “saving lives” (in the words of Kerri Sparling). “If we’re not there,” she implored the audience, “there’s a huge piece of the pie that is missing.” At minimum, she believes it is an obligation “to lurk, listen, and learn.” This was one of the strongest and most persuasive cases we’ve ever seen on the value of social media in diabetes – we give sincere kudos to Dr. Lee for being so forward-thinking (she has tweeted over 21,000 times!) and such a great advocate for the Diabetes Online Community (DOC). 

• With the help of real tweets, Dr. Lee made a case for why social media is useful in diabetes technology:
  
  • Keep abreast of real time diabetes technology issues.
  • To troubleshoot technology issues.
  • To learn how diabetes tech works in the real world..
  • To learn about design issues/flaws in diabetes technology.
  • To learn about novel real-world apps of diabetes tech (e.g., Kerri Sparling has used the asthma medication Flovent to eliminate rash from her CGM sites).
  • To learn about a patient designed future of mobile technology (e.g., Doug Kantor’s Databetes).
  • To witness the incredible creativity and hacking capabilities (e.g., Nightscout project/#WeAreNotWaiting/CGM in the Cloud; Dana Lewis’ DIY Artificial Pancreas).
  • To advocate as a community for individuals with diabetes (e.g., Strip Safely).
  • To connect our patients and families with online communities. 

Questions and Answers

Q: For many of us, the EHR is not only a useful tool, but a time sink and a billing tool. It’s very difficult to get information out. How can you get the companies that make EPIC and other EHRs to incorporate features so that the rest of us can use them? And for Dr. Lee, how do you keep the nutty stuff from getting shared and exploited? Is there a responsibility for us to know what is going on?

Dr. Ricardo Bellazzi (University of Pavia, Italy): This is an important question. When I started my activity in the hospital, main concern was that we were just putting data into the EHR and nothing came out. It was only for the government. The main thing was to start a project for designing a different structure to use or reuse the clinical data. To do that, we did a project funded here in the US: I2B2. It just finished. It’s an open source solution, implemented in Italy. It populates the data warehouse continuously.  It allows us to use this data for research purposes. The project I showed is a step forward. It collects not only EHR data, but also data from external sources. It’s a lot of work but it’s worthwhile I think.

Dr. Joyce Lee: If you see a lot of what’s online, there is a lot of great information and resources. I refer a lot of my new onset patients straight to online community, because they can offer things I cannot – I’m not a parent of a child with diabetes. There are misperceptions of wrong information. I think the problem is that we as healthcare providers have not been there. If Jenny McCarthy is out there saying there is no evidence, we as pediatricians need to be there saying, “Look at this evidence.” People still trust their healthcare providers more than anyone else. We need to be listening to the conversation; I don’t think you have to be an active participant. It’s important to have voices out there. If not, one side will win out.

Wearable Devices for Diabetes

Wearable Devices and Network Platforms for Artificial Pancreas and Advanced Glucose Management

Patrick Keith-Hynes, PhD (University of Virginia, Charlottesville, VA)

Dr. Patrick Keith-Hynes delivered a particularly forward-looking lecture on the potential of component AP systems to drive the future of glucose delivery and artificial pancreas development. He noted that such systems  distribute signal processing among the CGM, the pump, and an external controller, meaning that if any component fails, the system “degrades gracefully” and keeps patients safe. In his view, such a system is hugely advantageous for multiple reasons, including that: (i) it reduces the regulatory burden on the controller, enabling rapid iteration and improvement of the algorithm; and (ii) it places the algorithm outside the pump and gives it access to new types of sensor data, such as biometric information generated by wearable technologies. Indeed, Dr. Keith-Hynes spoke positively about the use of unobtrusive wearables (e.g., smartwatches) in closed-loop systems, as they minimize device burden while given patients a gadget they “want to wear.”

• Unobtrusive wearable-based bolus and AP interfaces can reduce the device burden and may encourage adherence. Dr. Keith-Hynes described bulky devices as one of the primary hurdles to closed-loop feasibility in current systems — in contrast, not only do smartwatches (and other similar technologies) reduce the hassle factor, but they offer the opportunity to integrate biometric data that can provide additional insight. Of course, the challenge rests in figuring out what biometrics to pull and how to use the in algorithms (e.g., Accelerometer data? Galvanic skin response?).
  
  • Dr. Keith-Hynes provided a neat glimpse at already ongoing efforts to integrate the DiAs closed-loop system with a smartwatch (Motorola’s Moto 360). Their prototype is able to display CGM data on the watch and alert users if a hypoglycemic event is pending. Dr. Keith-Hynes shared a vision in which the watch would also support external bolusing — users would be able to preconfigure scheduled boluses, receive a reminder on their watch (via Bluetooth), and confirm the bolus (also via Bluetooth). Dr. Keith-Hynes was quick to note that there is no guarantee such a concept would ever make it to market, though it is encouraging (and exciting) to see the creativity of researchers and commitment to patient-oriented solutions.
• According to Dr. Keith-Hynes, software frameworks (e.g., health and fitness platforms) have vast potential to enhance the performance of glucose-control systems. The ability to aggregate individual and population-based data is entirely untapped, though there is growing interest in this area. Dr. Keith-Hynes cited Apple’s new platform, HealthKit, as one of the few current systems that supports medical data in a secure way. As we the US healthcare systems increasingly focuses on value, the ability to integrate data from various sources will become more critical.

Product Demonstrations

Flash Glucose Monitoring

Steve Scott (Abbott Diabetes Care, Alameda, CA)

With the help of video and an on-screen user-interface, Mr. Steve Scott gave a valuable product demonstration of FreeStyle Libre. The videos showed product setup, sensor application, startup, glucose scanning, and sensor removal – all served as a great reminder of just how user-friendly and out-of-the-box ready the product is. The user interface demo focused on the on-device reader menus and reports, which include time-in-target, a logbook, ambulatory glucose profile (AGP) reports, and more; we were reminded of how much more comprehensive they are than those offered on CGM receiver/pump screens from Dexcom and Medtronic. This presentation was much more polished and consumer friendly than in the debut at EASD 2014, which focused much more on the accuracy. Though FDA was in the room today, Mr. Scott did not offer further details on the US pivotal study or an FDA submission – as of EASD, the US pivotal study was expected to begin before the end of 2014. He did say, as expected, that Abbott will try to pursue a replacement claim for the product (which it was not able to get for FreeStyle Navigator in the US). In Europe, FreeStyle Libre launched in October at webshops online.

Questions and Answers

Dr. John Pickup: Why didn’t you make it into a real time system?

Mr. Scott: We are positioning it as an alternative to blood glucose monitoring – giving people a greater insight into their glucose profile and variability. Our feeling is that CGM systems are available.

Dr. Pickup: What is the site of insertion?

Mr. Scott: Right now, we’ve only assessed one site, the upper arm. It’s a favorable site for many human factors reasons. As time progresses, we will explore alternative sites.

Q: You mentioned that you are designing this as an alternative to blood glucose – will you go after a replacement claim in US?

Mr. Scott: We’d love to approach approval for the system in the US. We will be trying to see what is required to go to that level and working with the Agency to see if that’s possible.

Q: But overseas, you are advertising it as an alternative to blood glucose?

Mr. Scott: This is a concept device for the US at the moment. Don’t want to go over what it does overseas.

Q: How many times can you scan in a 24-hour period?

Mr. Scott: It’s unlimited. You can scan as many times as you like.

Dr. Ken Ward: Was the MARD different on day one vs. day 14?

Mr. Scott: We were 14% on day one.

Q: For the near-field communication, how near does it need to be? Does anything interfere with that?

Mr. Scott: It works within about 2-3 inches. In our studies, it measures through big jackets. There is no issue with that.

Diabetes Technology Society Leadership Award

Diabetes Technology Society Leadership Award

David Klonoff, MD (Mills-Peninsula Health Services, San Mateo, CA) and Al Mann (CEO, MannKind, Valencia, CA)

Dr. David Klonoff presented the Diabetes Technology Society Leadership Award to Mr. Al Mann, the first ever two-time winner of the award (previously in 2004). Mr. Mann took the podium one day after his 89^th birthday, joking that he is “semi-retired – I work only 70 hours per week! [Laughter]” It’s all worthwhile, he said, because of the people that stop and thank him for things he’s done. Indeed, Mr. Mann told the story of a Buffalo teacher with diabetes that traveled all the way to DTM 2014 just to express his thanks – as a gift, the teacher handed Mr. Mann the following poem, written by Mr. Mann himself at age 11. Profound words of wisdom from someone so young, and a manifesto that Mr. Mann has followed his entire life. 

Young man I beg of you awake

And hear the error I did make.

I too did waste away my time

And did not wait ‘til in my prime

To realize that change was late,

So I must suffer now my fate.

 

Throughout my life the road’s been steep,

The fruits have been so few to reap.

If only I had listened then

When I was young to older men

The happiness I sought to earn

Might not have been so hard to learn.

 

It’s far too late to make amend

For life for me is soon to end.

And so my son don’t waste away

Those precious hours of every day.

Whate’er you can store up within

For life repays what you put in.

• Past winners of the Diabetes Technology Society Leadership Award include: University of Alberta’s James Shapiro (2001), CDC’s Eric Sampson (2002), US Army’s Karl Friedl and Carl Hover (2003), MannKind CEO Al Mann (2004), John Pickup (2005), John Patton (2006), Lutz Heinemann (2007), Boris Kovatchev (2008), William Tamborlane (2009), Medingo’s Ofer Yodfat (2010), Robert Vigersky (2011), FDA’s CDRH division, accepted by Jeff Shuren (2012), Viswanathan Mohan (2013).

 

--by Adam Brown, Varun Iyengar, Manu Venkat, and Kelly Close