FDA/JDRF/NIH Workshop on Innovation Towards an Artificial Pancreas

April 9-10, 2013; Bethesda, MD Day #2 Highlights

Executive Highlights

Hello from the NIH campus in Bethesda, MD and the second day of the FDA/JDRF/NIH Workshop on Innovation Towards an Artificial Pancreas. Wednesday’s presentations and discussion brought lots of detail on novel CGM and new AP approaches, with less of a focus on clinical data and study details.

The morning session on CGM was particularly valuable, headlined by valuable presentations from Dexcom’s Dr. Tom Peyser and Medtronic’s Dr. John Mastrototaro. There was a clear divide between Medtronic and Dexcom on the topic of CGM redundancy, a nuanced debate that is only beginning to emerge. Dr. Mastrototaro’s talk gave great perspective on the liability concerns of overnight closed-loop devices, shared a bit of regulatory flavor on the FDA’s review of the MiniMed 530G, and disclosed clinical data on the MiniMed 640G. Meanwhile, Dr. Peyser discussed minimum CGM performance criteria for the AP, the Gen 5 transmitter (available this fall under an IDE), and drew some of the heartiest laughs of the day with comical sports analogies to explain his views on redundancy.

Meanwhile, the focus on communication standards brought up on day #1 saw continued attention on day two. Dr. Joseph Cafazzo (Toronto General Hospital and the University of Toronto, Canada) convincingly discussed the efforts of industry members of the Continua consortium to adopt universal communication standards (IEEE, Bluetooth, and USB) for pumps, sensors, and BGMs. The approach seems quite encouraging and has strong support from JDRF. We think it’s only a matter of time before companies move further in this direction.

The afternoon roundtable discussion to conclude the meeting was most valuable, featuring many of the biggest names debating what the future holds for closed-loop delivery. Dr. Aaron Kowalski “threw down the gauntlet” and urged all of industry to get involved in this arena and conveyed his hopes on the regulatory and reimbursement fronts. Indeed, this will be a major funding initiative for JDRF this year, lucky for patients (we are not sure where patients would be without JDRF and the Helmsley Charitable Trust anchoring and helping guide so much activity). Dr. Kowalski put forward hope that any company that sells a pump will make a firm commitment to moving towards commercial PLGS systems in the immediate future.

One of our big takeaways from this meeting was the challenges industry faces in investing wholeheartedly into this arena. While the opportunity is wide open to help patients with a device as simple as predictive low glucose suspend, the regulatory environment still somewhat uncertain enough. It is hard to assess from the outside of course; we don’t see submissions or know any intricacies about trial delays, etc. We think this is particularly the case on the pivotal study front, where FDA’s final AP guidance, while valuable, is not specific as similar guidance on the drug side. Then, there’s the question of reimbursement, something that relates to labeling and ultimately, back to pivotal studies. Given the data to date, we agree with Dr. Kowalski and hope industry ultimately sees significant value in investing in closed-loop technology. We also see a blue ocean opportunity for creating compelling open- loop hybrid products – this could increase the utility of pumps and CGM significantly. We also hope more and more software and analytics come out soon to make managing diabetes easier and better – here’s to the closed loop long-term and more incremental improvements short-term. To be continued!

 

 

Detailed Discussion and Commentary

Future Devices and Other Innovative Approaches to Optimize a Closed-loop System

CURRENT AND FUTURE DEXCOM CGM SYSTEMS FOR ARTIFICIAL PANCREAS APPLICATIONS

Tom Peyser, PhD (Dexcom, San Diego, CA)

Dr. Tom Peyser discussed Dexcom’s broad pipeline of CGM innovation: 1) a review of previously shown G4 Platinum and G4 AP version data; 2) a brief discussion of the G5 smart transmitter (available this fall to closed-loop researchers under an IDE); and 3) pump partnerships with Tandem and Animas. Particularly valuable was his detailed discussion of redundancy; Dr. Peyser provided a competitive counterpoint to Medtronic’s redundant sensing approaches. We also appreciated his review of key CGM performance characteristics for the artificial pancreas. Now that the technology has come so far, we think it will be valuable for researchers, industry, and patients to hash out what level of system accuracy and reliability is good enough.

  • Dr. Peyser discussed Dexcom’s view of key CGM performance characteristics for the artificial pancreas: 1) accurate and reliable; 2) easy to use; 3) connectivity to AP controllers; 4) cost-effective and large-scale manufacturability; and 5) self-monitoring to assess signal fidelity. Dr. Peyser believes that the required level of CGM performance for the artificial pancreas should be seriously discussed within the closed-loop community. He proposed a MARD <10%, Clarke A- Zone points >85%, an occurrence of egregious errors <1% of the time, no pharmacological interferences, and an ability to prevent or identify fault conditions.
  • Closed-loop researchers have particularly appreciated the G4 Platinum’s improvements in signal transmission and reliability. Dr. Peyser specifically mentioned the system’s improved transmitter-receiver range (20 foot minimum) and no loss of transmission when the receiver is connected to a laptop or smartphone. He candidly told a story from the Seven Plus days, where AP researchers would call him in the middle of the night with signal transmission problems. Often, they would have to hold the receiver within six inches of the transmitter to get data.
  • Notably, the JDRF-funded version of the Gen 5 smart transmitter (ANT+ to a smartphone) will be available to closed-loop researchers this fall under an IDE. Dr. Boris Kovatchev specifically mentioned on day one of the workshop that the G5 will be used in two UVa Diabetes Assistant studies in 2013-2014: a multi-center outpatient trial of closed control (AP@home) and a multi-center home trial of closed-loop control (Jaeb Center and JDRF). As of Dexcom’s JP Morgan 2013 presentation, commercial launch of the Gen 5 was slated for 2014- 2015.
  • Dr. Peyser extensively addressed CGM redundancy, noting that it is “not a panacea” and must be put into a larger system context. He showed a humorous picture of many kids on a field aimlessly surrounding a soccer ball: high redundancy (many kids playing soccer) though low accuracy and reliability. He comically compared this to an Italian soccer player, who has low redundancy (just one person playing) but high reliability and accuracy. The same applies in a basketball analogy – the quest for redundancy does not mean it’s worth replacing a 60% shooter with two 30% shooters.
    • Applying this to the G4 Platinum, Dr. Peyser’s emphasized that the benefits of redundancy are significantly reduced with a more accurate sensor. He mentioned the oft-cited study from Drs. Jessica Castle and Ken Ward, which found accuracy benefits to using multiple redundant Dexcom Seven Plus sensors. Since the Seven Plus had lots of random error, such redundancy was an effective risk mitigation strategy. However, Drs. Castle and Ward repeated the study with the G4 Platinum and found a much lower benefit to using multiple sensors.
    • Many of the current sensor failure mechanisms are common to all sensors. These include improper SMBG calibration (one of biggest sources of error in Dexcom studies), wound response post-insertion, pressure induced sensor attenuation, data transmission problems, unexpected pharma interactions, and age-related bio-fouling.
    • Dr. Peyser argued that a system level redundancy strategy is a more effective approach to safety mitigation. First, intelligent CGM redundancy works to prevent severe adverse events by taking into account insulin dose history; the goal is to avoid hyperinsulinemia. System level redundancy also includes a physiological component –since CGM can reverse hypoglycemia unawareness, it could allow patients to detect an errant AP system on their own.
    • Sensor performance can be enhanced by self-monitoring of the sensor signal. This has been an integral part of the design of all Dexcom sensors. Algorithms can verify signal integrity, identify anomalies, and check for non-physiological rates of change. Ultimately, they can decide whether data is displayed or not (appearing as “???” on the Dexcom receiver). Dr. Peyser believes a sensor reliability metric would be key to provide to AP controller algorithms, as it would allow controllers to dose insulin more or less aggressively.
    • Dr. Peyser’s critical discussion of redundancy was a counterpoint to Medtronic’s enthusiasm. Dexcom is taking the view – perhaps rightly so – that since the G4 Platinum is more accurate and reliable, redundancy through multiple sensors is not needed. On the other hand, Medtronic has taken the view that using more than one sensor provides additional accuracy and reliability benefits, especially when the sensors are orthogonally redundant (glucose oxidase and optical). This is the first time we can recall seeing this dichotomy at a conference, and as CGMs begin driving insulin dosing, we think this issue is sure to come up again in the future.

 

PATHWAY TO COMMERCIALIZING CLOSED-LOOP SYSTEMS

John Mastrototaro, PhD (Medtronic, Northridge, CA)

Dr. John Mastrototaro provided a look at Medtronic’s stepwise plan to bring an artificial pancreas to market: 1) the Paradigm Veo/MiniMed 530G (no updates on the FDA review timeline); 2) the MiniMed 640G predictive low glucose management pump (expected to launch this year in Europe); 3) overnight closed loop and treat to range; and 4) fully closed loop. Dr. Mastrototaro emphasized that Medtronic is taking a cautious and risk mitigation approach to stages three and four, since these have higher risk – indeed, given Medtronic’s scale in the US alone (~300,000 patients on pumps = 100 million nights per year), even a small risk of an adverse event is still large in an absolute sense. The company is currently testing several fail-safe approaches and new algorithms in studies in Australia (and coming up in the UK).

  • Dr. Mastrototaro emphasized that closed-loop components must be treated as a system, especially in the context of commercialization. Although many researchers talk about seamlessly interchanging components, Dr. Mastrototaro argued that it’s not quite that easy. He explained that different pumps have different occlusion detection alarms, meaning that algorithms need to individually understand the unique parameters for each pump. On the sensor side, he used Dexcom’s interference with Tylenol as an example of limitations unique to certain CGMs (we note that data showed on the first day of the Workshop suggested this interference is not an issue with the G4 Platinum like it was for the Seven Plus). Dr. Mastrototaro’s system level discussion even mentioned the specific blood glucose meter used to calibrate a closed-loop system.
  • Low glucose suspend “is an improvement, but it’s not perfect. It won’t remove all hypoglycemia.” Dr. Mastrototaro described three basic failures of LGS: 1) times when the sensor is reading high and a low alarm is never triggered in the first place; 2) the sensor reads too low and erroneously suspends insulin, even though the blood glucose is actually higher (according to data from Dr. Bill Tamborlane, DKA is not a risk in these cases); and 3) suspension occursproperly, but the patient still goes low (e.g., a patient takes far more bolus insulin than is needed, and suspending the pump will not stop hypoglycemia).
  • Medtronic’s predictive low glucose management pump, the MiniMed 640G, will “likely be launched this year in Europe.” This was less specific timing than remarks in the company’s F3Q13 call, where EU launch was expected this summer. We’ll be interested to hear in the company’s May 21 F4Q13 call whether a summer launch is still on track.
    • Dr. Mastrototaro showed data from 22 experiments of the MiniMed 640G, where 14 hypoglycemia events were prevented. The mean glucose nadir was 79 mg/dl and the mean suspension time was 92 minutes. He did not give further study design details or any sort of comparison to Veo or open-loop therapy. The last data we heard on the MiniMed 640G came at EASD 2012 – a computer simulation of the new pump algorithm reduced the number of hypoglycemia events (<70 mg/dl) by 18% and the average duration of hypoglycemia by 50%, a significant improvement over the Veo’s corresponding reductions of 1% and 28% (see page three of our EASD Diabetes Technology report at http://www.closeconcerns.com/knowledgebase/r/9f88794c). In our view, predictive low glucose management would be very beneficial for patients and represents a very achievable step near-term.
  • Dr. Mastrototaro believes that the biggest AP safety concern is a large CGM error sustained for a long period of time. By contrast, he does not view transient sensor compression artifacts as a big worry, since the pump would suspend insulin and then resume quickly (i.e., assuming that the sensor artifact results in a transient dip in blood glucose). This represents a ~20-30 mg/dl rise in blood glucose, which would subsequently be corrected by the system.
  • Dr. Mastrototaro believes overnight closed loop is the next logical step after low glucose suspend and predictive suspension systems. Since patients are not dealing with meals, overnight insulin delivery is only provided by the basal rate. This means much less aggressive insulin delivery (“one daytime meal equates with the total insulin you would give in the whole overnight period”) and a greater opportunity to mitigate the risk of sensor inaccuracy. Dr. Mastrototaro was also positive on the potential of treat to range to limit postprandial peaks.
  • Commercializing an overnight closed-loop system is “a bit tricky,” with “lots of concerns from a legal perspective and risks of liability.” He explained that assuming Medtronic has approximately 300,000 people on insulin pumps (as an aside, based on 450,000 US pumpers per Halozyme’s most recent estimates, this translates to ~67% market share by volume for Medtronic, in line with the company’s market share by sales in our most recent model). That many patients on pumps translates to over 100 million closed-loop nights per year. Even if sensors have serious issues on one in one thousand nights, that’s still over 100,000 nights per year that Medtronic pumpers could be in trouble on an improperly designed overnight system. Put differently, based on STAR-3 data of 13 severe hypoglycemia events per 100 patient years, which is the lowest rate generated thus far, that’s still 40,000 severe hypoglycemia events for US Medtronic customers each year.
    • Said Dr. Mastrototaro, “When we’re looking at commercializing [an overnight] system, we’re adding all sorts of fail safe mechanisms”. These will include sensor checking algorithms and mitigations against calibration errors. Medtronic’s clinical trials will assess fake sensor and meter values to make sure the system is safe. The company has started one trial in Australia using the new system withfail-safes, and another is starting in the UK within a month. The basic idea is to have five different algorithms running in the background.

 

MEDTRONIC’S CURRENT AND NEXT GENERATION SENSING AND DELIVERY DEVICES

Rajiv Shah, PhD (Medtronic, Northridge, CA)

Dr. Rajiv Shah’s presentation focused on Medtronic’s use of sensor redundancy and electrochemical impedance to improve accuracy. Data from a flat ribbon probe with electrodes on both sides showed that sensor readings can differ from one side of the sensor to the next, suggesting that localized cellular environments affect accuracy. As such, Medtronic is investigating the use of glucose-independent electrochemical impedance spectroscopy to determine when a sensor starts to fail. If impedance values fall outside of an “ideal” or predicted impedance band, information from the sensor can be de- emphasized. Thus, by fusing data from redundant sensors and using electrochemical impedance information to de-emphasize readings from failing sensors, Medtronic hopes to avoid sensor inaccuracy caused by localized effects. In other pipeline news, Dr. Shah noted that Medtronic was in the midst of finishing its clinical evaluation of its integrated sensor/infusion set in support of regulatory submission. Dr. Shah’s ATTD presentation gives additional detail on Medtronic’s pipeline products – see page 57 of our ATTD full report for detail: https://closeconcerns.box.com/s/tf5n9kn7dgxz7jdxmmn2.

 

BD’S NOVEL SENSORS AND INSULIN DELIVERY

Kerstin Rebrin, MD, PhD (BD Medical, Franklin Lakes, NJ)

Dr. Kerstin Rebrin provided updates on BD’s proprietary glucose binding protein (GBP)- based optical sensor in development. The system is currently in its second generation and Dr. Rebrin noted that the most immediate challenge going forward was to further miniaturize the optical device. Diving into the technical detail, Dr. Rebrin explained that the protein folds when glucose binds to it, resulting in the quenching of fluorescence. BD measures two wavelengths of light – blue and green – and uses the ratio of these wavelengths to reduce signal to noise ratio. Next, BD applies a non-linear calibration curve and time delay correction. (The system has a time delay of ~five minutes.) Dr. Rebrin was encouraged by initial simulation data and the sensors overall profile – she noted a good in vivo interference profile, reduced insertion trauma, consistent placement, signal stability over time, fast warm up time (<20 min), and favorable wear comfort. As of ATTD, the system was being tested in two clinical studies: a 24- hour study through UVA/JDRF in 12 patients and a 29-patient, three-day study in Canada. For greater detail, see page 36 of our full report https://closeconcerns.box.com/s/tf5n9kn7dgxz7jdxmmn2.

 

INTELLIGENT CATHETERS THAT COMBINE HORMONE DELIVERY WITH AMPEROMETRIC GLUCOSE SENSING

Kenneth Ward, MD (Legacy Research Institute, Portland, OR)

Before discussing his ongoing work to integrate sensing technology into a catheter, Dr. Kenneth Ward explored whether insulin could indeed be delivered in the same microenvironment in which glucose is sensed. Turning to the literature, a microdialysis/microperfusion study showed that when there was no physical separation between glucose sensing and insulin delivery, the degree of local glucose reduction was fixed (~15-20%) and irrespective of insulin rate (Lindpointer et al., Diabetes Care 2010). A study of subcutaneous insulin delivery in a swine model that examined sensor data near and far from the site of delivery led the authors to conclude that the test to test variation between sensors substantially exceeded the effect of the distance between glucose sensing and insulin infusion (Rodriguez et al., Diabetes Technol Ther 2011). Said Dr. Ward, subcutaneous insulin seems to have less of a localized effect than one would predict. He explained that one of two competing fates befall injected insulin: 1) the insulin acts (and is degraded) at the fat cell; or 2) insulin is absorbed into the blood stream. Due to rich adipose blood flow rate, negative cooperativity (whereby very high local concentrations of insulin inhibit insulin action), and the comparatively inefficient insulin uptake by adipose tissue (vs. muscle uptake) Dr. Ward argued that absorption is the primary fate of subcutaneously injected insulin. As such, Dr. Ward believes that an integrated glucose sensor and catheter is feasible. He is working to develop such a device through collaboration between his company Pacific Diabetes Technologies and Oregon State University. The idea is to use a flex circuit to dispose glucose sensors on a flat surface that can be wrapped into a catheter (i.e., each catheter is encased by a glucose sensor). While the system is early stage (pre-animal testing), we can’t help but be excited by its potential to reduce patients’ care burden by decreasing the number of devices worn.

 

NON-GLUCOSE OXIDASE-BASED SENSING TECHNOLOGIES

Natalie Wisniewski, PhD (Chief Scientific Officer, Profusa; Medical Device Consultancy, San Francisco, CA)

Dr. Natalie Wisniewski gave an overview of the pros and cons of non-glucose oxidase-based glucose sensing technologies. Her presentation focused on fluorescence and had a clear takeaway: there is a bright future, in her view, for fluorescence-based sensing chemistries alone or in combination with glucose oxidase. She highlighted two significant benefits of fluorescence: a lack of glucose and a lack of oxygen consumption. Dr. Wisniewski was positive on Senseonics’ recent implantable data (MARD of 12% over several months), and wondered what the outlier values were. She also highlighted the “really encouraging” chemistry of BD’s glucose binding protein CGM, as its accuracy may be better in the hypoglycemic range. She did not give any sort of timeline or prediction on who would come to market first. She covered a few other non-glucose-oxidase technologies (direct electro-oxidation, non-invasive, holographic crystal, osmotic pressure sensing, MEMs), highlighting that all are early stage and “not ready for prime time.”

 

LONG-TERM, FULLY IMPLANTED, SELF-CONTAINED SUBCUTANEOUS GLUCOSE SENSOR: RESULTS FROM CLINICAL EVALUATION AND APPLICABILITY FOR CLOSED- LOOP SYSTEMS

Joe Lucisano, PhD (President and CEO, GlySens, Inc)

Dr. Joe Lucisano discussed GlySens’ efforts to develop an implantable continuous glucose sensor. The GlySens sensor uses a dual detection method, whereby the system monitors the enzymatic reactions of both glucose oxidase and catalase (which breaks down hydrogen peroxide, a byproduct of the glucose oxidase reaction). Dr. Lucisano reviewed results from the human feasibility trial of the first-generation device; data was first presented at the Diabetes Technology Meeting (see our discussion on page 29 at https://closeconcerns.box.com/s/3b1bj4dx1e7wu8kgrixa). Data were presented: (1) showing operation of the fully implanted sensor for month-long periods without need for recalibration and (2) affirming patient acceptance of the device. The feasibility study also revealed that the sensor’s data transmission to the external receiver did not perform at the maximum desired distances (data transmission was often disrupted at night when the receiver was on a bedside table) and that, in some cases, the tissue pO2 would drift outside the operational range and preclude glucose readings (background oxygen levels are used to calculate glucose readings); however, Dr. Lucisano commented that these two issues have been corrected for in GlySens’ second-generation design. The company expects to begin clinical testing for its second-gen system this year.

 

THE PERITONEAL CAVITY AS A SITE FOR GLUCOSE SENSING: A FEASIBILITY STUDY

Dan Burnett, MD (Theranova, San Francisco, CA)

Dr. Dan Burnett believes that sensor failures are a byproduct of the space in which they rest as opposed to the sensor technology itself. As such, Dr. Burnett is exploring the viability of the peritoneal cavity as a sensing site. Unlike the subcutaneous tissue, he explained, the peritoneal cavity has a constant core temperature and is physically protected from external mechanical stress. Further, it has minimal tissue response to biocompatible materials, a reliable blood supply, and proven history of safe use for other medical devices. Dr. Burnett described his team’s initial work in juvenile non-diabetic pig models comparing sensor lag time during subcutaneous vs. peritoneal glucose sensing. Indeed, intraperitoneal latency was shorter than subcutaneous latency with respect to time to half maximal values (p <0.001). Dr. Burnett also recently presented the data at the 13th Annual Rachmiel Levine Diabetes and Obesity Symposium – see page 49 of our report for detail: https://closeconcerns.box.com/s/ib6v1obcvl6u4ajpmowg.

 

PANEL DISCUSSION (EXCERPTS)

Dr. Barry Ginsberg: Some sensors are more accurate than others. Is there a way to pick them out post-manufacturing?

Dr. Tom Peyser: We actually would like to pick out only the most accurate sensors and sell them. We check performance of every sensor we manufacture in vitro. But we haven’t found a good way to predict which of those will be good in the body. Our approach is to try to reduce variance in manufacturing. There was a lot of variance on the Seven Plus. That’s been a big focus of ours with the scale up. The concept of the MARD distribution is to highlight that at a MARD of 10-12%, or even at 14-15%, there are some sensors on the left of the distribution – these may be more accurate than BGM. There are also sensors on the right side, which can cause problems for patients. We are exploring ways to identify good performing sensors, but also addressing manufacturing.

Dr. Ginsberg: There was a large study in 1993 that examined the accuracy of BGM in the hands of patients. The average error was 13%, and those were meters.

Dr. Aaron Kowalski: Tom’s presentation highlighted that G4 AP is a software improvement. According to the data, it conveys significant improvements in terms of accuracy. Is there a way at FDA to incorporate software-based improvements into industry systems faster? Isn’t there a faster way than filing PMA supplements over and over again?

Ms. Arleen Pinkos: FDA has accepted software modifications with very little clinical data, but it depends on the nature. In the case of Tom, I thought it was a membrane change?

Dr. Peyser: The membrane change was from the Seven Plus to G4 Platinum. G4AP is just a software improvement. We are looking forward to discussions with you and others for ways of expediting that. From my perspective, Aaron, the changes are in the calibration algorithm. We would expect to have to do a clinical study. Maybe not as much of a clinical study as we did for the G4 Platinum originally. That would be up to discussion with the Agency.

Ms. Pinkos: We often hear someone tweaking their algorithm for improvements. You might need a bridging study to show what kind of effect it had on performance.

Dr. John Mastrototaro: If you are going to modify the labeling with improved accuracy, you need clinical data and a PMA supplement. It’s the same thing – you’re improving sensor performance and want to have data to back it up and modify labeling.

Ms. Pinkos: Another option includes taking old data and running it through the algorithm retrospectively.

Q: You mentioned hypo events at a rate of 13 events per 100 patient years. What is the bare minimum target for sensor accuracy and serious adverse events? A single event can be catastrophic.

Dr. Mastrototaro: 13 events per 100 patient years came from our STAR-3 trial using sensor augmented pump therapy. The DCCT and other trials are many times higher than that. In sensor performance for the closed loop, we’re looking at it differently than MARDs. You could do closed-loop with 20% error if you consistently had that error all the time. The issue is big mg/dl errors for sustained periods of time. What we focus on, and we have tens of millions of days of sensor data, is periods when the sensor is grossly off for extended periods of time. That can be a catastrophic failure. We try to figure out what aspects of those events we can mitigate. So we’re mitigating calibration errors, for instance. If you can identify when the CGM is inaccurate, then you just won’t be in closed loop at that time. The big issue for us, however, is how many times you are going to have the big errors sustained for a long period of time.

Dr. Gary Steil (Children’s Hospital, Boston, MA): We’re starting a closed-loop study where we take YSI glucose values and randomly throw in the types of errors John just talked about. The target is 120 mg/dl. The YSI error will be 30 mg/dl, which pushes it down to 90 or 150 mg/dl. The intention is to do closed loop through nighttime and breakfast. If YSI thinks you’re at 90 and you’re really at 120, that’s a sustained 24-hour error. All glucose errors are not created equally. Most of the errors that people are incredibly concerned about need to be taken into account by robust algorithms.

Dr. John Mastrototaro: Another example is the sensor gets pulled out of the body or the sensor has died or failed. That’s different from the sensor just reading low.

 

Elements for a New Generation of Devices/Technologies

ADVANCEMENT OF THE ARTIFICIAL PANCREAS THROUGH THE DEVELOPMENT OF DATA AND COMMUNICATION STANDARDS

Joseph Cafazzo, PhD (Toronto General Hospital and the University of Toronto, Canada)

Dr. Joseph Cafazzo gave a nice update on the work towards standardizing BGM, CGM, and insulin pump communication, a desperate need cited throughout the Workshop. After making a strong case for the value of standards, Dr. Cafazzo discussed the work of Continua, a consortium of 200 member companies that includes a handful of diabetes players: Bayer, Dexcom, Medtronic, Sanofi, JDRF, and Roche. Continua calls for adoption of the IEEE standards, Bluetooth and Bluetooth low energy, and USB. The blood glucose meter standard has already been published and is in its second revision. Meanwhile, the insulin pump standard has been drafted and is in balloting, while the CGM standard is in draft form. These standards are released to manufacturers on an annual basis. Looking forward, Continua hopes to develop a standard for dual-chambered insulin pumps. We wonder whether companies could be incentivized to join Continua, perhaps by either FDA or JDRF. Overall, we love the focus on device standardization and believe it has massive potential to help the entire field, especially AP research.

  • Dr. Cafazzo made a strong case for the benefits of standardization for industry, patients, and regulators. Arbitrary data formats and radio transport systems result in redundant, wasteful efforts in building individual interfaces for individual products (e.g., artificial pancreas systems). Dr. Cafazzo believes standards can encourage new entrants (researchers and companies), help create an innovation ecosystem, and build a competitive advantage. From a regulatory perspective, standards mean less variability in products considered by FDA. This also means more transparency, industry consensus, and an ability to address security issues. Dr. Cafazzo also appealed to common sense, everyday reasons for standards – there are clear standards for planes, trains, automobiles, all forms of construction, Internet, and data communication. Without these, widespread innovation and use would not be possible.
  • The proposed standards are not intended to be performance requirements for the artificial pancreas. Dr. Cafazzo emphasized that they “are not like accuracy requirements for SMBG,” and they are not about post-market mixing and matching of components. The intent is for the standards to be used in pre-market research when companies are developing products.

 

CLOSED-LOOP INSULIN DELIVERY IN DIABETIC PIGS USING A SMART BIOMATERIAL DEVICE

Margaret Joan Taylor, PhD (De Montfort University, United Kingdom)

Dr. Margaret Taylor described her team’s effort to develop a biomaterial device for closed-loop insulin delivery. In contrast to conventional designs, the device utilizes no sensor or algorithm. Rather, glucose sensitive gel that is implanted into the peritoneal cavity governs insulin release (the insulin rests in a depot within the gel). The gel contains polymerized ConA and dextran, which are competitively displaced in the presence of glucose. This causes the gel to form a sol, thereby increasing the material’s permeability and releasing insulin directly to the liver. The gel is housed in a pebble-shaped device with ports that allow for ex-vivo refilling. Dr. Taylor described her teams’ investigation of the device in pigs; the study was first presented at ATTD (see page 30 at https://closeconcerns.box.com/s/tf5n9kn7dgxz7jdxmmn2). While the study started with 10 pigs, only one pig was used in the analysis (pigs were lost for myriad reasons, including anesthesia-related complications, under dosing of streptozotocin [used to induce diabetes], and peritonitis). However, Dr. Taylor was optimistic about the pig’s glucose profile with the implanted device and she encouraged the audience to keep their minds open to solutions that were neither biological nor electronic in nature.

 

BIOARTIFICIAL PANCREAS: CHALLENGES AND OPPORTUNITIES

Cheryl Stabler, PhD (University of Miami, Miami, FL)

When it comes to islet cell transplants, said Dr. Cheryl Stabler, it’s all about “location, location, location.” Dr. Stabler explained that approximately 60% of islet cells die within the first week of transplant due to initial inflammatory responses and that the remaining islets often experience metabolic burnout and a smoldering immune response overtime. The high inflammatory response of the subcutaneous tissue has motivated Dr. Stabler and her team to investigate alternative sites. She believes that the omental pouch is a promising site because it has portal drainage, is richly vascularized, can be accessed minimally invasively, and has immune suppressive qualities. Next, she proposed that silicon scaffolds could further optimize the islet cell microenvironment by providing physical protection (i.e., the islets would be housed within the scaffold). Potentially, scaffolds could also enable localized drug delivery, in situ oxygen generation, and co-delivery of helper cells, all of which could improve an islets’ cell survival chance. Microencapsulation of the cells could also help improve survival by camouflaging the islets from the immune system – her team is currently exploring a microfluidic technique to create a thin conformal coating. Certainly, there are myriad challenges to overcome for long-term successful islet cell transplantation; however, we are encouraged to see Dr. Stabler systematically addressing the issues that have come to light with current techniques.

 

MICROCHIP-BASED SENSING AND DELIVERY

Robert Farra (MicroCHIPS, Waltham, MA)

MicroCHIPS is manufacturing an implantable microchip that houses multiple reservoirs for drug or sensor storage; the device is implanted just below the subcutaneous tissue. The device provides long- term protection for the reservoirs’ contents. It can release the drug or expose the sensor on demand via an electronic signal such that medicine can be delivered remotely. Dr. Robert Farra envisions that the technology could enable longer-term glucose sensing or redundant glucose sensing (i.e., multiple sensors could be exposed and when those sensors start to fail, electronic signals could be used to open new reservoirs and thus, expose new sensors). Additionally, Dr. Farra believes that the device could be a good delivery technique for glucagon (or could even house both glucagon and glucose sensors). The company’s next-generation device will have 200 reservoirs (vs. 20 in the previous gen) that are 1.0 mg in size (vs. 0.5 mg). We look forward to following the company’s pursuit of potential diabetes applications.

 

ENGINEERING A CELL-BASED GLUCOSE MONITOR

Eric Schreiter, PhD (Janelia Farm Research Campus, Howard Hughes Medical Institute)

Dr. Eric Schreiter gave a basic-science-focused talk on engineering a glucose responsive fluorescent sensor protein. The basic idea is to express this glucose-responsive fluorescent protein in a group of cells by safely delivering it through a gene transfer or autologous cell transfer (e.g., take a skin biopsy, get the sensor in, and then re-implant the cells). Ultimately, the researchers plan to build a wearable spectroscopic device to measure the fluorescence. Dr. Schreiter and colleagues recently built a thermus thermophilus glucose/galactose binding protein (TtGBP) sensor and optimized it for the physiologic glucose range. It undergoes a ~300% fluorescence increase from hypoglycemia to hyperglycemia levels of glucose. Dr. Schreiter’s rushed concluding slide indicated that the sensor still needs improvement on a few fronts. Still, despite the very early stage of this approach, it was quite interesting and we hope to hear more.

 

Roundtable Discussion: Perspectives for the Future

PANEL DISCUSSION

Kenneth Ward, MD (Legacy Research Institute, Portland, OR); Barry Ginsberg, MD, PhD (Diabetes Technology Consultants, Wyckoff, NJ); Todd Zion, PhD (Cofounder, SmartCells); Natalie Wisniewski, PhD (Medical Device Consultancy, San Francisco, CA); Howard Zisser, MD (Sansum Diabetes Research Institute, Santa Barbara, CA); Aaron Kowalski, PhD (JDRF, New York, NY); Courtney Lias, PhD (FDA, Silver Spring, MD); Guillermo Arreaza, MD (NIH, Bethesda, MD); Rich Bergenstal, MD (Park Nicollet Health Services, Minneapolis, MN); and Robert Vigersky, MD (Walter Reed National Military Medical Center, Washington, DC)

Dr. Bergenstal: What are the hopes, expectations, and needs in the short term to keep this momentum going? What are we going to expect and hold each other accountable to?

Dr. Kowalski: I am going to throw down the gauntlet. I started out the meeting talking about the need for delivery to patients. I want to throw down the gauntlet to industry. We’re working well with industry, but I would like to see within the next 24 months every pump that is speaking to a sensor have low glucose suspend.

Dr. Bergenstal: What will that take?

Dr. Kowalski: We heard a lot of stretch goals here. As a simple safe thing to do, predictively turning off pumps could be transformative. Medtronic is on that path and hopefully the FDA is working with them in the States. Other companies need to make a commitment to this. This will be a major funding piece for JDRF this year and we could put it out to the industry. I hope that any company that sells a pump will make a firm commitment to at least PLGS systems in the very near term.

Dr. Lias: We’d like to see that happen too. What we get out of this type of interaction is everybody in the same room. We get a lot of information, can look at bigger goals, and everyone else can kind of hear what’s going on. I share your point of view that that would be a great thing. We will do what we can to continue that.

Dr. Zion: Anyone can cut down on hypoglycemia. As you get more aggressive, you get more and more hypoglycemia. It’s a laudable goal to turn off pumps, but we should look at whether you’re losing control. The bar needs to be set quite high. I’d like to see more talks look at other variable like MAGE and incidence of hypoglycemia.

Dr. Kowalski: I agree with you and I disagree. I had this talk at FDA. I grew up in a house where my brother had a lot of severe hypoglycemia. I saw a lot of ambulance trips and I have given a lot of glucagon injections. I personally think that the hypoglycemia/A1c tradeoff should be a decision that clinicians and patients make. My brother’s A1c is 6.8%. Would he be willing to sacrifice and go to a 7.3% and not have two hospital trips this year? That should not be an FDA decision. That’s a clinician decision. That tradeoff is in the guidance right now. If you set the bar too high, you’re tying the hands of the medical practitioner and patient.

Dr. Lias: I think that’s the point Arleen was making yesterday. We care about safety, but the real issue is whether there is enough information about the device so people can make informed decisions. Maybe they will be able to label the device to say that hypoglycemia is reduced, but that there is an A1c trade off.

Dr. Arreaza: That’s a kind of massive community work. We, as a government agency, cannot be doing any advocating work. We rely on other groups to lobby congress. Constituents of Congress members have tools to make the community aware of problems and to put pressure on their Congressman. The NIDDK remains committed to supporting basic and applied research and we are going to continue doing that independent of the resources we have available. Even if the Type 1 diabetes special program is not available, we will find a way to continue supporting research. We hope some of those questions on the board today will be answered by the end of this forum. For example, what are the biggest gaps in technologies? We are able to, in some way, identify gaps through internal processes, but we need help from the scientific community to put together more efficient programs and perspectives to lay a plan for the upcoming years. For example, the second question [“How much focus in future research is needed on understanding the biological interactions (e.g. device-tissue interface, immune response) vs. engineering elements (e.g. algorithms, better polymers)?”] – we are already funding, but if you can help us identify in a more precise fashion those key aspects to getting to this goal for a working wearable artificial pancreas, we want to continue supporting those efforts.

Dr. Wisniewski: I love Aaron that you threw down the gauntlet for an immediate artificial pancreas product. We need short-term practical goals. But remember members of the research community are also working on more advanced technologies that lay the groundwork for five to ten years from now. We need to make sure that we are appropriately funding the advance research that will get us to a “wear-and- forget” device that has wide patient and physician adoption. We need to support a strong research foundation that moves us beyond percutaneous needles that have to be replaced every week and that patients have to calibrate several times a day. From a Silicon Valley viewpoint, funding models of the past to support R&D to develop truly advanced, innovative products are dead. We (medical device start-up industry) very much rely on DARPA, NIH and foundations. We need to ensure that pathway is laid for long-term fully implantable AP. We should have the race in the short-term, but let’s not lose sight for the long-term.

Dr. Bergenstal: Do you have any advice for us on how to renew the Special Diabetes Program funding? It got funding for one year – how can we get that going for three years?

Dr. Ward: I was going to say that system integration is completely key to all of this. I heard several people say that the problem in the AP is not the algorithm or science or sensor or pump. It’s communication failures. We talk about going home with the AP. The key question is how many times does that doctor, tech, or engineer walk home and fix the system? How often do they have to call up the patient on the phone? We’re talking about reliability and simplicity. We must also reduce and combine elements. The dual chambered pump is a perfect example, as is integrating sensors into catheters.

Dr. Zisser: I think that will come. Currently, researchers are using off the shelf products. We are trying to build what we think in our minds will work. Anything we can do to get standards is good, though it’s a long process. Eventually, phones, computers, and the systems will be on the pump itself.

Dr. Ward: Do we wait for that time to release a product? Can’t we make it now?

Dr. Zisser: Making it and getting it released are two different things. A rate-limiting thing is power consumption. You’re communicating all the time. These systems aren’t designed with that capability. When I look back on where we were a couple years ago, we’ve done a lot of what we hoped we would do. One of my takeaways from this meeting was the variability of insulin over days and sensors over days. Anything we can do to decrease that is beneficial.

Dr. Vigersky: I recall someone mentioning the bell-shaped curve of IQ and we have that for physicians in their ability to understand systems and prescribe them appropriately. Do we need a full proof system or should we allow only certain people to subscribe them who have met certain standards?

Dr. Kowalski: Right now there is a bell-shaped curve and right now every one with type 1 diabetes has to manage their diabetes or they die, so they do it. What’s clear is that glycemic control is not great. It gets back to what Courtney was saying – we need to test these devices and define clearly what they can do, then provide tools to well-trained physicians, just like pumps and sensors are today. I come back to the comparator of where we are right now. We have a point of time in diabetes where we made a lot of progress, but there is still a ways to go.

Dr. Bergenstal: We’re talking about patients with diabetes and human factors. What’s simple and what can we use? There are some people with diabetes in the audience. I don’t want to put them on the spot, but perhaps I could ask Kelly if she might have a comment?

Ms. Kelly Close, MBA (Close Concerns/diaTribe, San Francisco, CA): We hope the field will keep in mind that incremental changes are immensely valuable as patients. Without the first backpack insulin pump (you all know that picture!), we wouldn’t have small pocket sized pumps now. Without the GlucoWatch, we wouldn’t have today’s amazing CGM. On the artificial pancreas, let’s also keep this perspective – the first product won’t be perfect and has no need to be. What we’re doing today as patients is SO far from perfect. It would be amazing to see excellent progress on technologies that make open loop therapy much better and less of a hassle. That could be smarter CGM, software that helps adjust insulin dosing, or technology that better incorporates into our daily lives.

Along with that technological progress, we absolutely hope we will have seen far more commercial progress in the coming years. We hope that companies and regulators both become less worried about liability. We all know that there are so many accidents that happen EVERY DAY with this crazy drug called insulin. There are so many accidents that happen with cars and driving, or even just people going to bed in their own homes every night. They aren't accidents that are attributed to FDA or to a company, but they are due to the difficulty of dosing insulin. Let's agree that every single accident won't disappear, but let's leave open the possibility that many of them will.

We hope we'll see more creative thinking about how to prove cost-effectiveness. The environment has never seen so much cost pressure. So many people want to see a modern day DCCT. We now have sensors that would make that happen. There are so many brilliant people here who know how to design trials and how to show benefit – we hope to see more collaboration like with the JDRF CGM trial that changed so many of our lives.

Imagine a world where the AP is available to everyone who needs it. A world where we wake up in the morning, our BG is reset. A world where we don't have to stop and think all the time. A world where we get a guaranteed A1c in target that will protect us from complications. Imagine the 'health dividend' that the AP will create – that would have an enormous long-term impact on healthcare costs. Imagine equally much change as we have seen since our last meeting. We look forward to watching our world, following it, writing about it, and to preparing to live a life that is more normal, healthy, and productive and predictable. [Applause]

Dr. Boris Kovatchev (University of Virginia, Charlottesville, VA): I want to take the next 45 minutes to say… just kidding [laughter]. The system approach should be the most important thing we focus on now. There were only three talks that mentioned it – John Mastrototaro’s talk, Joe Cafazzo’s talk, and probably mine. At the end of the day, the AP is a system. If we want to get there quickly, we have to do some things. I agree with Howard that the system is important, but I disagree that everything needs to be built into the pump. That’s only looking at one dimension of the pump – basic computing in a single device. It’s the horizontal version. The vertical version is distributed computing between these devices, an intermediate device (e.g., a smartphone), and the cloud. To get there, we need a base. One question is do we need a medical grade operating system. I think the answer is yes. I think we should get there ASAP. Do we need core testing facilities? I think the answer is yes as well. We are capable of establishing system testing facilities that may be independent of anybody and would use in silico validation of systems. This allows fast and rapid development with real components that are linked to a simulator. So there are two things that we need: the base and the testing facility for rapid evaluation of system functionality.

Dr. Arreaza: To establish the core testing facility, will it will be necessary to develop a consortium of scientists working together with industry to standardize this process?

Dr. Kovatchev: Correct yes, it’s cooperative work. That’s why we need to decide this here in this room.

Dr. Kowalski: I do think clinicians are a huge barrier. If you look at CGM adoption, CGMs are tremendously powerful tools. Most of people in this room are the few people that are actively prescribing them. We need tools to facilitate clinician adoption. I talk to the JDRF team about our goals – improve glycemic control and make patients lives easier by reducing burden. What will help clinicians and help facilitate adoption? We need data and tools such as the Ambulatory Glucose Profile. That’s an output to interpret information in a short office visit and give good recommendations. We aren’t going to have a fully automated, fully closed loop tomorrow. For now, there’s going to be this interaction and you are going to have to go to your doctor. We need to have the types of tools Rich is working on. We need to reduce the burden on the health care providers as well as the patients. Many doctors don't prescribe CGM to many patients (who could benefit) because they find it tedious, don't get reimbursed for their time, and feel they don't get much out of it.

Dr.: If I can provide an analogy – for osteoporosis, you must take an exam and get certified to read DEXA scans to get reimbursed. Perhaps JDRF could set up some sort of course or certifying exam.

Dr. Zisser: This is also done in fellowship programs.

Dr. Lebinger: What elements of artificial pancreas testing of artificial pancreas component testing could and should be standardized? We see a lot of data today comparing various sensors to blood glucose levels. What should the comparison be? Some people use arterialized venous blood, regular venous blood…venous blood is used to diagnose diabetes but fingersticks/capillary blood testing is used to manage diabetes. There are postprandial differences between these different matrices. What should be the standard comparison?

Dr. Zisser: The difference you are referring to in the postprandial phase is in this direction (gestures up)? You could have postprandial in this direction (gestures down)?

Dr. Lebinger: Yes, up.

Dr. Zisser: If the controller and sensor says 180 mg/dl vs. 210 mg/dl, I don’t really care so much. It’s when you get down around euglycemia, that difference is very important. With CGM we calibrate with fingersticks and we use venous YSI for reference. There’s always going to be noise in each one of those compartments.

Dr. Lebinger: Some are using arterialized venous blood for YSI and some are using venous blood for YSI.

Dr. Zisser: What is that difference?

Dr. Lebinger: I have papers with me I can show you after.

Dr. Ward: Arterialized is a little higher.

Dr. Zisser: A little. There is no true glucose. If one says 105 mg/dl and one says 95 mg/dl, is that wrong?

Dr. Lebinger: It can be up to about 11% difference postprandially.

Dr. Kowalski: I always get caught up in this argument. I give Dexcom a lot of credit. Dexcom focused on hyperglycemia and hypoglycemia. I call this a clinical chemistry argument. Let’s not miss the forest from the trees. Sometimes we get so hung up on this accuracy question and individual system components. To make an analogy, if I put my cruise control on at 55 mph, am I going to be worried about the performance characteristics of my fuel injector? At this meeting, my concern is that people are getting hung up in things that may not be absolutely critical or that important. Errors may be completely washed out. In a clinical trial, we’re not asking how much insulin is coming out of the cannula. I would urge the community not to get so focused on the little pieces and miss the big picture.

Dr. Zisser: I think the discrepancy is important enough in the hypoglycemia region. But there is inconsistency in how CGM is compared to reference.

Dr. Kowalski: Don’t get me wrong – I totally agree that we do need standardized outputs for these trials.

Dr. Wisniewski: I appreciate your viewpoint Tessa. I think that’s a very focused question. I don’t have a definitive answer and it seems the science doesn’t…

Dr. Lebinger: I was saying that when you are evaluating your sensors, we should have a standard for reference.

Dr. Wisniewski: There is a big need for that. As we are developing new sensors, we want to be able to compare the next one to the next one. You want to make a fair comparison, but we need a level playing field – it really is a hindrance to development.

Dr. Moshe Phillip (Tel Aviv University, Petah Tikva, Israel): At my clinic, I don’t care that the sensor is accurate. What I care about is patients.

Dr. Lebinger: It becomes a question when you’re sensing different areas, especially intraperitoneal sensing vs. interstitial fluid.

Dr. Ginsberg: If you have sensors measuring different areas of the body, they are different sensors. If you want to do head to head comparisons, you need to do third party testing.

Dr. Kovatchev: Testing and standardizing the outcome of testing of components is mostly done already. It’s done by many people in the room including, Barry and myself. We spent several months five years ago producing a document that is now the continuous sensing standard. It has seven different tests for how you test continuous glucose sensors and that is out there. Lets focus on what Dr. Moshe Phillip said.

Dr. Lias: I want to go back to the forest. We really do try to look at the point of whatever is in front of us. We will use a clinical endpoint if we think that’s appropriate. If it’s about accuracy, we would look at that. We are very interested in hearing if there are suggestions on standardization. We take an approach of fit for purpose.

Dr. Sanjoy Dutta (JDRF, New York, NY): I want to add one more big tree into that forest. Can we discuss pivotal or definitive clinical trials for the artificial pancreas? How will it help the Agency make a decision? How would you design such a trial? What will you be looking for?

Dr. Lias: Our thoughts on AP trials are most eloquently stated in the guidance document. It has a lot of “if this, then that.” There are a lot of different devices. If you’re using CGM as an endpoint, maybe CGM accuracy is more important. There’s a lot of flexibility for intended use. That’s why this discussion is helpful to us – it helps define what is the device for and what is the appropriate trial designed for.

 

-- by Adam S. Brown, Kira Maker, and Kelly Close