Memorandum

Medtronic collaborating with FDA on regulatory path for MiniMed 640G – May 12, 2014

Executive Highlights

  • Medtronic and the FDA have reportedly been working very collaboratively on the clinical and regulatory path towards approval of the MiniMed 640G predictive low glucose management system. As we understand it, there is potential to have the device approved and on the US market as soon as 2015.
  • Our report reviews clinical data on the MiniMed 640G; discusses the impact of the device on the pump/CGM competitive landscape; includes some key questions for the field; reviews our themes from ATTD 2014; and curates our recent artificial pancreas reports.

As we understand it, Medtronic and the FDA have been working quite collaboratively on the clinical and regulatory path towards approval of the MiniMed 640G predictive low glucose management system. According to comments from Patricia Shrader (VP, Corporate Regulatory and External Affairs, Medtronic) at the Food and Drug Law Institute’s annual meeting, there is potential to have the device approved and on the US market as soon as 2015 – this represents the first US launch timeline we’ve ever heard on this next-gen automated insulin delivery device. This timing would also represent a notable acceleration from Dr. Fran Kaufman’s comments at Clinical DTM – in April, she noted that Medtronic was working to file an IDE, US studies could begin by the end of 2014, and would last ~18 months. As of Medtronic’s F3Q14 call in February, international launch of the MiniMed 640G was expected to occur by October 31, 2014, though that was a three-month delay from timing given at JP Morgan.

The news, if true, is very exciting from a patient perspective. First, the journey to the landmark approval of the MiniMed 530G in September 2013 lasted four years, as the pump was launched outside the US in more than 50 countries in September 2009. That process included a 15-month review at the FDA, the ASPIRE in-clinic study (which Dr. Satish Garg has repeatedly the most challenging study of his career), the 247-patient ASPIRE in-home study (ongoing during the FDA’s review, but not included in the submission or the label), and insulin pump quality systems problems. The potential for an abbreviated development path and review of the MiniMed 640G would represent a huge step forward for the FDA and for patients. Certainly, it does line up with the FDA’s recent announcement of an expedited PMA pathway for breakthrough medical devices. Whether the MiniMed 640G would formally qualify for this path is less important than the Agency trend it signals – a commitment to collaboration, flexibility, and a drive to get products into patients’ hands faster.

Many in the field have expressed particular excitement for the near-term potential of predictive low glucose suspend management – noted JDRF’s Dr. Aaron Kowalski at the April 2013 NIH/FDA/JDRF Artificial Pancreas Workshop, “I want to throw down the gauntlet to industry … 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…I hope that any company that sells a pump will make a firm commitment to at least PLGS systems in the very near term.” Unquestionably, the MiniMed 530G was an important first step towards closing the loop, but the data on the MiniMed 640G looks significantly better on reducing hypoglycemia (see below). In addition, Medtronic’s MiniMed 640G will feature a redesigned pump platform (simpler user interface, color screen, and waterproof) and use of the new Enlite Enhanced CGM sensor.

Below, we review clinical data on the MiniMed 640G; discuss the impact of the device on the pump/CGM competitive landscape; share some key questions for the field; review our themes from ATTD 2014; and curate links to our recent artificial pancreas reports.

Clinical Data on the MiniMed 640G

  • At ATTD 2014, Dr. Thomas Danne reviewed the results from the PILGRIM study testing Medtronic’s predictive low glucose management (PLGM) system. Twenty-two adolescents (mean age: 15 years; mean A1c: 8.0%) exercised with the PLGM system to induce a drop in blood glucose. Of the 16 patients who reached the hypoglycemic threshold for PLGM activation, predictive suspension was successfully activated in 15 of the experiments and prevented hypoglycemia (reference blood glucose ≤63 mg/dl) in 12 of the 15 experiments (80% of the time – “a big success”). Mean sensor glucose at predictive suspension was 92 mg/dl, mean suspension time was 90 minutes, and mean sensor glucose upon insulin resumption was 97 mg/dl.
    • The PLGM algorithm used a 30-minute prediction horizon and suspended insulin delivery when a predictive threshold <80 mg/dl was reached. As background, the PLGM algorithm suspends basal insulin for at least 30 minutes and for a maximum of two hours – the resumption of insulin delivery between 30 minutes and two hours is variable and is based on current and predicted sensor glucose.
  • Simulation data has suggested the PLGM algorithm can reduce 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%. The PLGM suspended insulin delivery at an average blood glucose of 83 mg/dl (vs. 69 mg/dl for the Veo) and the average max glucose after insulin resumption was 150 mg/dl (vs. 160 mg/dl for the Veo). As measured by YSI, the algorithm falsely suspended about 20% of the time. The data was derived from the FDA-approved UVA/Padova computer simulator (n=300 virtual patients) and was presented by Dr. Barry Keenan (Medtronic Diabetes, Northridge, CA) at EASD 2012.

Impact of the MiniMed 640G on the Pump/CGM Competitive Landscape

  • Near-term, approval of Medtronic’s MiniMed 640G system stands to most significantly impact Animas and Tandem. Based on public information, Tandem and Animas have the nearest term CGM-integrated pumps coming to market in the US – the Animas Vibe has been under FDA review for the past 14 months, while submission of the Tandem integrated pump will occur in June 2014. The Animas Vibe has already been launched internationally and based on past comments in Dexcom financial results calls, has competed well with the MiniMed 530G.
  • The MiniMed 640G will also launch with the next-gen Enlite Enhanced sensor, which would certainly represent additional competition for Dexcom. Right now, Dexcom is ahead of Medtronic’s Enlite on accuracy based on the published head-to-head data we’ve seen thus far (with the caveat that head-to-head studies are small). The new Enlite Enhanced sensor has an 80% reduction in implanted size; a new sensor adhesive to reduce skin irritation; a new electrode pattern with the goal of more consistent performance throughout the sensor life; and an improved sensor to transmitter connection. We assume these improvements would result in better accuracy, though data has not been shared yet on this front.
  • Medtronic may have some persuasive marketing messaging if the clinical data for the MiniMed 640G looks particularly strong. We imagine a message along the lines of, “A 60% reduction in hypoglycemia” would be hard for many to resist, particularly for parents of children with type 1 diabetes. What will be particularly illuminating to see is how the MiniMed 640G affects Insulet, since the company has historically been strong in pediatrics (per the 1Q14 call, its fastest growing demographic was <18 years). It’s worth noting that over 70% of Insulet patients come from MDI – we do think Insulet will be somewhat affected by the launch of the MiniMed 640G, though the OmniPod’s tubeless value proposition will be hard for any traditional pump to completely compete against, regardless of automation.

Key Questions

  • How to manage patient expectations? Expectations are sky high for the artificial pancreas, and we believe the field can learn a lot from the early days of CGM – do not overpromise! Early adopters of AP systems will likely be extremely hands-on patients, which could actually present an additional development challenge from the get-go – or opportunity. Companies should keep this in mind as they develop marketing and training materials for systems – that will be key in managing expectations.
  • How much automation is the right amount? There will be a spectrum of insulin delivery automation in the coming years, as companies move to predictive suspend, treat-to-range, and fully automated control. The question is to what extent patients will be willing to relinquish control as systems get increasingly advanced. We expect there will be a range of views depending on various patients’ priorities. Some will not want the “hassle” and some will want to micro-manage the decisions and some will be at various points along a “control-relinquish” continuum. Human factors and customizability will play important roles in this piece of the puzzle.
  • What is the potential market for an AP? Given the low rates of CGM penetration (~10% of US type 1s) and pumps (~25-30% of US type 1s), the key question is how many patients will be willing to wear an AP? We believe that both open-loop as well as closed-loop systems will ultimately dramatically improve the utility of CGM and pumps (“the killer app” for both, in the words of Dr. Steven Russell), and so we believe the number of patients that could be helped is vast. Already, even though there are a very high number of patients who advocate wearing pumps, it is established that insulin delivery as it stands today is sub-optimal for many patients.
  • Is there a business model for automated insulin delivery devices? No one quite knows what price premium AP systems will command and what payers will be willing to cover. A related question is how payers will tradeoff the higher cost of systems with reductions in hypoglycemia and/or improvements in A1c? What level of benefit will they like to see? Will the quest for reimbursement be easier than it was with CGM? We know that JDRF is working hard on this front and will certainly be using a lot of what was learned driving reimbursement for CGM.
  • Will academic groups pursue commercialization of closed-loop systems? This is a topic we address at length in our report below – The Artificial Pancreas – Current Status and Future Prospects in the Management of Diabetes. Broadly speaking, when the commercialization of the artificial pancreas was originally discussed (going back over a decade), the notion was that commercial entities would ultimately be able to leverage academic research to build products that would be made available to patients through companies. However, we’ve increasingly seen more interest in commercialization from academic researchers. While companies like Medtronic and Animas have their own closed-loop systems in development, academic institutions have also developed their own portable systems in the research setting. Ultimately, we assume that academics will partner with companies, but this may not be a foregone conclusion. ​Academia can be more nimble in terms of creating and iterating a system, though companies have expertise in bringing products to market and supporting them after approval (distribution, customer service, reimbursement, FDA regulations, etc.). More questions on this topic discussed below.
  • Following predictive suspend, is there a downside to 24/7 automation vs. overnight-only? This question was one of the top highlights of the EASD Diabetes Technology Conference in February, where Dr. Aaron Kowalski said, “I think it’s a harder regulatory pathway to do overnight closed-loop control only vs. day/night closed-loop control.” Dr. Kowalski reiterated several concerns that the regulatory path will be very difficult for night-only closed-loop control, which originally came up in hallway chatter at ATTD: (i) the FDA will likely focus on what defines “night” vs. “day”; (ii) patients would try to use the night-only system during the day – and what defines night for one patient isn’t the same for everyone (e.g., those who work nightshifts); and (iii) there doesn’t seem to be any downside to treat-to-range control running in the background during the day (i.e., on top of manual boluses for meals), even if it is a pretty wide range. Dr. Roman Hovorka agreed that these were valid points, and voiced his view that “we need to ask companies like Medtronic how they feel” about this issue. When it comes to moving hundreds of thousands people onto closed loop control, Dr. Hovorka said he believes the risk is lower with overnight-only systems. Dr. Kowalski has great direct experience meeting with the FDA, including very close collaboration to write the final AP guidance; we think this may come down to groups being able to work best on nocturnal control but having some movement (even broad) toward tighter daytime control with some very basic automation (predictive suspend, treat-to-range). This is a discussion on which we expect to hear continued evolution in the coming year as companies and academic groups come to greater consensus about commercialized products could look like – which will be first is certainly of big interest and we believe having many alternatives ultimately will be a major win for patients.

Themes from ATTD 2014

  • Nocturnal closed-loop was the focus of multiple talks at ATTD 2014, with a number of researchers (University of Virginia, DREAM, Cambridge) noting their belief that this is the next step after predictive low glucose suspend. We would note this is in contrast to previous years (and the original 2009 JDRF artificial pancreas roadmap) that put a treat-to-range/hypo-hyperglycemia minimizer as the next move forward in automated insulin delivery rather than a singular nighttime focus. At ATTD 2014, many researchers (e.g., Drs. Boris Kovatchev, Roman Hovorka, Moshe Phillip) presented impressive, long-term (up to six weeks), outpatient data demonstrating that overnight systems are safe and highly effective in bringing down glucose levels and reducing the risk of hypoglycemia. Notably, studies are also beginning to show that closed-loop overnight has positive ripple effects the following day. The risk-benefit of such systems seems much more favorable, particularly because current insulin therapy overnight is particularly suboptimal; for example, Dr. Hovorka highlighted that nocturnal insulin requirements are highly variable within the same patients from night-to-night (ranging from double the pre-programmed basal rate to half the pre-programmed basal rate within the same week), as well as throughout the night.
  • Another clear theme from this year’s ATTD could be termed the “academic/commercial chasm”how will closed-loop systems in the academic research setting translate to commercialized products? Some researchers now have systems that are well tested and characterized in the research setting (e.g., DREAM, BU/MGH’s Bionic Pancreas, UVa’s DiAs) but it’s unclear how these will translate into commercial products. Ultimately, most believe that a control algorithm running on a smartphone is valuable for research purposes, but not feasible for a final commercial product. With that in mind, the next step seems to be integrating algorithms (either from academia or industry) into pump/CGM systems. But this brings up a vast array of questions:
    • Will insulin delivery companies (Medtronic, Animas, Tandem, Roche) in-license academic technology?
    • How hard will it be for multiple companies to work together to get a closed-loop system approved (e.g., Dexcom CGM + another company’s pump)?
    • Will academic groups start their own companies to build commercial products? If so, how will regulators perceive such efforts, especially for manufacturing and validation?
    • What will it take for regulatory bodies to be comfortable with interchangeable closed-loop components (i.e., choose your devices and plug in whatever algorithm you want – Cambridge, DREAM, UVa, etc.)?
    • On the other hand, will approvals hinge on unified systems?
  • Historically, the ultimate translation from academic research to commercial products has always been an open question, and certainly one that JDRF and the Helmsley Charitable Trust have worked to address through industry partnerships (e.g., Medtronic, BD, Dexcom). Now, it’s clear that the academic research has advanced far enough; the next question is what are the subsequent steps and how will groups get there. For example, how could academia think about the following?
    • What components make up their first-generation systems?
    • Are the components “exclusive”? With future generations, can more components be used?
    • What will FDA demand in terms of validation for manufacturing?
    • What will FDA require in terms of proving manufacturing capabilities?
    • Who will fund these needs? How much funding is necessary?
    • How clunky will the early systems be? What will satisfy patients? How broad is the range of acceptability in form factor for the earliest systems?
  • With research progressing quickly and more robust closed-loop systems moving to the outpatient setting, other ancillary questions are coming up with increasing frequency:
    • What patients are optimal for different closed-loop systems?
    • Should trials enroll more patients with severe hypoglycemia? How would this be defined?
    • How will newly diagnosed patients cope with closed-loop technology?
    • Given the potential for broad use and millions of patients exposed, what’s the best way to evaluate the safety of closed-loop systems?
    • How should regulators balance comprehensive safety evaluations without being overly burdensome?
    • How will companies perceive the liability of commercializing closed-loop technology?
    • What length of pivotal study is necessary to understand a system’s risk, given the potential for millions of patient-years of exposure once a device is commercialized?
    • How should patient expectations be set? What is optimal?
    • What term(s) should be used – “automated insulin delivery” for the early systems, “closed loop” for the later systems? Where do the terms “artificial” and “bionic pancreas” fit in?
    • Are healthcare providers ready for closed-loop insulin delivery?
    • What role should remote monitoring play?
    • Should commercialized closed-loop technologies include remote monitoring by default and let patients/providers choose whether to use it?
    • Will clinical trials undersell the benefits of closed-loop systems, as patients in these trials are typically motivated and well managed at baseline?
    • How will closed-loop insulin delivery systems be priced?
    • What will payers demand for higher reimbursement? How will A1c improvement be perceived? How will less mild/moderate/severe hypoglycemia be perceived?
    • How will payers evaluate anecdotal patient experience and quality of life?

Close Concerns Recent Artificial Artificial Pancreas Reports

  • The Artificial Pancreas – Current Status and Future Prospects in the Management of Diabetes - Drs. Peyser, Dassau, Breton, and Skyler share valuable commentary on future AP development, advocate for creation of a new company to integrate best-in-class tech, and discuss the latest in CGM and debates over smartphones and role of glucagon. This is a super packed piece, where we also briefly discuss the latest Diabetes Care that has all sorts of automated insulin delivery discussion - it is heartening to see all the top-notch scientific literature amassing these days on this controversial and important subject area.
  • FDA proposes new expedited access program for medical devices that address unmet medical needs - On April 22, the FDA announced an exciting new expedited access PMA program for medical devices that address unmet needs. Notably, the program will feature earlier and more interactive engagement with FDA staff, a collaboratively developed plan for collecting data to support approval, earlier approvals with more data collected in the post-market setting, involvement of senior FDA management, and a priority review. Based on a read through the two associated draft guidance documents, posted here and here, we believe automated insulin delivery devices may qualify (lots of thoughts in our report about why and what the path going forward will look like). The devil will be in the details, but broadly speaking, the program’s goal and the draft guidance language reads highly encouragingly from a patient and industry perspective.
  • Full Interview and Abridged Interview with David Panzirer and Dana Ball - A must-read for anyone in diabetes that includes fascinating conversations on the history of the Helmsley Charitable Trust and the T1D Exchange; the future of type 1 diabetes; the funding/philanthropy landscape; diabetes technology and the artificial pancreas; diabetes advocacy and so much more. A true gold mine of wisdom from two of the field’s most widely respected leaders.
  • ATTD 2014 Days #3-4 - Key themes and unanswered questions for artificial pancreas development; outpatient data from UVA, Stanford camp study, BU/MGH bionic pancreas, DREAM; What company will close the loop? Medtronic’s first redundant CGM sensor data; Dexcom on how CGM could save a payer $59-321 million/year
  • ATTD 2014 Day #2 - Dr. Ed Damiano shares Beacon Hill, Summer Camp study compelling topline results; Dr. Steve Edelman on power of Dexcom arrows, new Medtronic Enlite vs. Dexcom G4 Platinum study - who came out on top? Tandem on A1c improvement, training time
  • ATTD 2014 Day #1 - Accuracy/design updates on Abbott's Flash Glucose Monitoring; FDA webcast presentation on artificial pancreas safety (FDA keeps getting better); do we need remote monitoring? Has Medtronic's next-gen Enlite already launched in the EU?

--by Adam Brown and Kelly Close