EASD Diabetes Technology Conference

February 26-27, 2014; Dusseldorf, Germany; Highlights – Draft

Executive Highlights

Guten abend from Dusseldorf, Germany where the EASD Diabetes Technology conference just wrapped up. This small 1.5-day meeting of ~120 attendees was mainly focused on regulatory approval of devices in Europe and globally. Talks addressed all the main areas of diabetes technology, including the artificial pancreas, insulin pumps, CGM, and BGM accuracy. Our report is organized into top ten highlights, followed by a handful of detailed write-ups.

In today’s artificial pancreas-focused morning session, an interactive Q&A included Dr. Aaron Kowalski’s view on why the regulatory path for overnight-only closed-loop is likely harder than for 24-hour systems. Meanwhile, Medtronic’s regulatory expert Mr. Mark O’Donnell provided an afternoon highlight in discussing the four main ways the company is working to make insulin pumps safer – it was outstanding to see how patient-focused these were and we really stopped and thought about how lucky we were to be patients today, rather than decades ago, even in spite of all the reimbursement barriers. On the first day of the meeting, we also listened carefully to a whole session devoted to the new ADA/EASD Diabetes Technology Committee and its upcoming Statement on the Evaluation of Insulin Pumps – no specific details were shared on the statement itself, which will be ~6,000 words and likely published in Diabetologia and Diabetes Care in June or July. (Six thousands words is about the length of this EASD report! Lots to cover…)

In glucose monitoring, the new and very stringent FDA standards for point-of-care meters came up several times. Speakers Drs. David Sacks (NIH, Bethesda, MD) and Dr. Guido Freckmann (University of Ulm, Germany) made it clear that the new in-hospital accuracy requirements are too strict – Dr. Sacks believes “no meter” can meet the requirements and if the FDA does not make them more lax, “there will be no glucose meters approved in the future.” This echoed some of our writing from Vienna – we absolutely agree and were happy to hear the thought leaders say so. Dr. Freckmann’s talk on reference methods was less outspoken but still agreed – it’s not clear if we even have a reference standard accurate enough to approve meters at the proposed level of accuracy. We also enjoyed an evidence-based talk from Dr. Hans De Vries on whether CGM benefits A1c, severe hypoglycemia, and pregnancy, as well as what cost-effectiveness estimates have not taken into account (see honorable mention #1 in our ATTD 2014 Day #3-4 Report for a great presentation on CGM cost-effectiveness).

More broadly, a jam-packed session delved into the current legislative status and proposed changes to the medical device approval process in Europe – said EASD President Dr. Andrew Boulton, “This system was designed in the last century and belongs in the last century.” Overall, the changes seem to be moving more slowly than we imagined (see below), though speakers from Eucomed and IQWiG still expressed concerns and even a bit of pessimism. The EASD has clearly signaled its intention to make the CE Mark process stricter (going back to its March 14, 2013 press release; see pages 10-17 of our EASD 2013 Diabetes Technology Report for a great symposium on the European device regulatory process), though it was clear from this session that it’s going to take a while – the earliest the legislative changes could be signed into law is likely early 2015 (they are still under debate in member states). With an expected four to five year transition period for industry, the law wouldn’t take full effect until ~2020. We found this session most useful in the questions it raised – see the appendix for a complete review.

Our top ten highlights below also include the ADA’s Dr. Robert Ratner on the most important thing diabetes technology researchers and companies need to do; new data on insulin pump failures from France; the power of Sweden’s national diabetes registry; and what a British Member of Parliament with type 1 diabetes is doing to raise the policy conversation about diabetes.

Top Ten Highlights

1. “I think it’s a harder regulatory pathway to do overnight closed-loop control only vs. day/night closed-loop control.” – Dr. Aaron Kowalski (JDRF, New York, NY). This particular comment in Q&A was the highlight of a morning artificial pancreas session that primarily reviewed data presented at ATTD 2014. As we wrote in our report at the time, nocturnal closed loop was a major theme at ATTD in February, with a number of researchers (University of Virginia, DREAM, Cambridge) noting their belief that this is the next step after predictive low glucose suspend. Overnight closed loop is next, according to many, 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. We heartily agree, given our recent experience in the UVA trial; of course, it’s up in the air how fast all the groups will move. In this Q&A, Dr. Kowalski reiterated several concerns that the regulatory path will be very difficult for night-only closed-loop control that came up in hallway chatter at ATTD: (i) the FDA will likely focus on what defines “night” vs. “day”; (ii) patients would try to the night-only system during the day – and what defines night for one patient isn’t the same for everyone; and (iii) there certainly isn’t any downside to closed-loop 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; it seems to us like a “hybrid” model may be easiest. 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. 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.

2. Medtronic Diabetes’ VP of Regulatory Affairs Mr. Mark O’ Donnell provided a most valuable update on what Medtronic is doing to make insulin pumps safer. His talk emphasized the need to make pumps easier to use (especially through user interface design), to involve patients earlier in the design/development process, to communicate much better with patients, and to rethink product design and risk as insulin delivery becomes more automated. Medtronic is focused on four key areas to ensure pumps are safer moving forward: (i) modifying risk analysis procedures and increasing patient communication (e.g., notifications to customers); (ii) developing a systematic way to listen to customers (e.g., earlier involvement in product design – we’re hearing a lot more from companies on this front, exemplified most recently at Sanofi’s Partners in Patient Health Day (see our report)); (iii) increasing reliability testing beyond intended use cases (e.g., water resistance, drops); and (iv) moving from passive to proactive post-market surveillance (MiniMed 530G customer outreach program). See the appendix for more details on each.

3. Dr. David Sacks (NIH, Bethesda, MD) commented that “no meter” can meet the new FDA BGM standards for in-hospital/point-of-care use. Said Dr. Sacks, “These are incredibly stringent [standards]…I hope that the FDA listens to the complaints, because clearly there will be lots… I think that it’s going to be very difficult for manufacturers to meet these criteria. If they don't make them more lax, there will be no glucose meters approved in the future.” As a reminder, the point-of-care BGM standards, released on January 7, call for 99% of measured values to fall within ±10% of reference (>70 mg/dl) and within ±7 mg/dl for <70 mg/dl. Additionally, 100% of results must be within ±20% of the reference method (>70 mg/dl) or ±15 mg/dl (<70 mg/dl). Dr. Sacks emphasized that for 99% results to fall within 10%, the coefficient of variation cannot exceed 3.8%. However, central lab analyzers typically have a coefficient of variation just under 2% – in other words, the guidance does not leave room for the imprecision of reference methods, and no reference method has zero imprecision. Dr. Sacks calculated that for a device to provide a 99.99% level of accuracy, one would need to take ~30,000 measurements. Dr. Guido Freckmann (University of Ulm, Germany) concurred with Dr. Sacks, showing data for one of the most accurate meters he has studied (he would not divulge what meter it was) – shifting the bias by ±5% took the meter from passing to failing the new FDA point-of-care standards. Dr. Freckmann called the new FDA point-of-care standards “very difficult to fulfill” and wondered if it is even possible without a clearly defined and traceable measurement procedure. We wrote about this during ATTD (see item #8 of our ATTD 2014 Day #2 Report); there certainly seems to be growing consensus on this issue.

4. An afternoon session provided a very high level overview of the new Draft EASD/ADA Statement on the Evaluation of Insulin Pumps. No details were shared on the statement itself, which will be ~6,000 words and likely published in Diabetologia and Diabetes Care in June or July. ADA 2014 will have an official press conference about the joint statement, to be followed by an entire session at EASD 2014. The aim of the initial insulin pumps statement was somewhat vague, though the short overview talks in this session addressed pre-market evidence, clinical studies, registries, and post-market reporting/surveillance. We’re still not totally clear on what the statement will entail and what would be a home run in the eyes of the committee (6,000 words is not much!), though we believe some of the major goals include: raising the level of conversation around pump safety; establishing clearer guidelines for regulators; helping patients and HCPs choose pumps; and to push industry to collect more robust data to support approval and reimbursement. Dr. Anne Peters’ (USC, Los Angeles, CA) talk was a particular highlight of the session – she was critical of the FDA’s adverse event reporting system, which does not provide nearly enough data to assess the safety of insulin pumps. ADA’s Dr. Robert Ratner also shared valuable concluding remarks on what’s missing in the field – see the appendix for both talks.

  • This statement is the product of the newly formed (October 2013) ADA/EASD Diabetes Technology Committee (AEDTC), which hopes to support patients, HCPs, manufacturers, regulators, and policy makers by writing official statements about medical devices in diabetes. The first statement is on insulin pumps, though subsequent statements will address SMBG, CGM, and the artificial pancreas. The committee includes six members: Drs. Richard Bergenstal, Anne Peters, and Alexander Fleming from the US, and Drs. Lutz Heinemann, Reinhard Holl, and John Petrie from Europe.

5. An entire session focused on the current legislative status and proposed changes to the medical device approval process in Europe – said EASD President Dr. Andrew Boulton, “This system was designed in the last century and belongs in the last century.” The session’s main speakers included Mr. John Brennan from Eucomed (a medical device trade association that represents manufacturers), Dr. Stefan Sauerland from IQWiG (Germany’s reimbursement authority), and Dr. Alan Fraser from the European Society of Cardiology (disappointingly, the expected speaker from the European Commission could not attend). All the speakers highlighted the very complicated and bureaucratic EU regulatory and lawmaking process, which weaves member countries, notified bodies, and other stakeholders in a very complicated web (we saw at least three different PowerPoint diagrams). Talks repeatedly emphasized the broken regulatory system, a discussion that built on the dedicated session at EASD 2013 (pages 10-16) and last year’s EASD press release (“Avoiding a Medical Device Disaster in Diabetes”). The proposed legislative changes to tighten the regulatory approval process are currently under debate at the EU member states level; given upcoming parliamentary elections and the regulatory path forward, the earliest the changes could be finalized into law is likely early 2015. According to Dr. Fraser, the law likely wouldn’t take full effect until ~2020, as there would be a 4-5 year transition period for industry. Broadly speaking, the three speakers were in favor of many of the proposed changes (e.g., stronger supervision of notified bodies, unannounced site visits, better device traceability, post-market surveillance, more transparency, etc.), though all identified particular issues and areas of concern (e.g., RCTs should not be mandatory, the scrutiny and clinical data requirements are unfair, the process is still too random and unpredictable). Dr. Sauerland was particularly pessimistic on the law and shared his view that “nothing will really change.” Overall, we found these talks most instructive in the questions they raised. See the appendix for a complete summary of what we saw as the key debates – Is reimbursement becoming the new approval? What level of evidence should be required to approve medical devices? Should medical devices be treated the same as pharmaceutical products? Who else should be involved in the regulatory approval process and to what extent? How will funding constraints impact regulatory reviews? These issues have come up at various meetings in previous years and Dr. Boulton framed the evolution expertly in our view.

6. Dr. Hans De Vries (Academic Medical Center, Amsterdam, Netherlands) shared a valuable literature review on the benefits of CGM for reducing A1c, improving severe hypoglycemia, and pregnancy. Studies to date support the technology’s use to lower A1c by ~0.5% (“undeniable” evidence at the level of systematic review and meta-analysis) and to improve severe hypoglycemia (though with weaker evidence than A1c reduction, with just one RCT and one case report at this point: Ly et al., JAMA 2013 and Choudhary et al., Diabetes 2013). Data does not currently exist to support CGM use in pregnancy (two conflicting RCTs: Murphy et al., BMJ 2008 and Secher et al., Diabetes Care 2013), though JDRF is currently funding a very large multinational trial looking at CGM use in pre-pregnancy (planning) and in full-term pregnancy.

  • Dr. De Vries also shared his view on cost-effectiveness and why the previous estimate for CGM of $100,000/QALY (Huang et al., Diabetes Care 2010) may be an overestimation. Two factors that are not typically taken into account could improve the cost-effectiveness of CGM and bring it closer to the commonly used cutoff of $50,000/QALY. First, patients often wear CGM sensors longer than the indicated wear time (Luijf et al., DT&T 2013), thereby reducing the cost of using the technology. Second, cost-effectiveness studies usually employ intent-to-treat analyses, a principle long used with drugs (i.e., there is no way to monitor if the drugs are being taken or not). However, CGM is fundamentally different from drugs because it’s easy to tell who is using and not using the device (i.e., by looking at the uploads) – said Dr. De Vries, “We are only paying for a device that is used.” As such, a per-protocol analysis may be more justified with CGM. With these two points in mind, Dr. De Vries concluded that cost effectiveness “may be less of a problem” than with the initial Huang et al. analysis from the JDRF CGM trial. We believe better cost-effectiveness data and clinical studies are critically needed in CGM, as the technology has improved markedly since the JDRF CGM trial.
  • Dr. De Vries called CGM “arguably the most important evolution in the field of diabetes technology in the last 10-15 years, and perhaps in the whole field of type 1 diabetes.” This echoed comments from Dr. Steve Edelman in the Middle East earlier this week (see our Emirates Diabetes and Endocrine Congress 2014 Report). Before beginning his talk, he noted that he has taken both the PRO and CON sides in countless CGM debates over the past 10 years. While he always accepted the CON side when it was assigned to him in the past, he recently accepted an speaker invitation only if he got the PRO side. Dr. De Vries admitted that “the evidence has increased and the technology has matured” to a point where the CON side would be very challenging. This was terrific to hear during his very evidence-based talk and serves as a real testament to how far the field has come since the earlier generation products.

7. Dr. Robert Ratner’s talk (“The View of the ADA”) emphasized the lack of quality clinical data in diabetes technology. Said Dr. Ratner, “Let us be an evidence-driven profession; not an anecdotal data-driven profession.” Dr. Ratner ran through the 2014 ADA  Standards of Medical Care in Diabetes and pointed out key changes and gaps in evidence. Notably, the ADA removed the specific testing frequency recommendations for SMBG (four times per day in type 1 and once per day in type 2) – the Association found that payers were taking these too seriously and only reimbursing that specific number of strips. While SMBG has “Category B” evidence (“A” is best), Dr. Ratner called CGM “more problematic.” Most importantly, CGM has “Category E” (“expert consensus or clinical experience”) evidence in patients with hypoglycemia unawareness or frequent hypoglycemia. Dr. Ratner acknowledged that the ASPIRE trial will be incorporated into next year’s Standards of Care, but “we still rely far too much on evidence category E.” Regarding data for insulin pumps, there is “nothing” in type 2 diabetes and a “paucity of data” to inform the choice between MDI or pump therapy. Dr. Ratner pushed the academic and industry representatives in the room to answer these clinically relevant questions. To conclude, he highlighted the importance of labeling language, which has really informed reimbursement for CGM. The technology’s approval as an “adjunct” therapy (i.e., a confirmatory fingerstick is required) made it “relatively easy” to get it approved, but has presented a roadblock to obtaining reimbursement from CMS for Medicare and Medicaid patients. Notably, ADA asked CMS to merely create a new benefit category for CGM – not to actually reimburse it – a request that was swiftly denied. Dr. Ratner pressed industry to “take the long view” and collect the critical clinical data that show devices’ value.

8. Dr. Isabelle Guilhem (CHU Rennes, France) presented updated data (2008-2013) from a long-term prospective study of insulin pump failures in France. The group’s first study (2001-2007) was published in 2009 in Diabetologia – of the 640 pumps distributed to 252 patients, 36% (n=232) had some sort of malfunction, including 103 “complete pump failures” (44% of the malfunctioning pumps). The rate of malfunctions was 25/100 pump years, the median pump survival time was 30 months, and Medtronic was significantly better than the other three brands. In the updated preliminary data presented today, 314 new pumps were distributed from 2008-2011 (76% Medtronic pumps; Roche was not included in this early look at the results). Malfunctions occurred in 70% of the pumps (n=220), roughly double the prevalence seen in the earlier study; however, the rate of “complete pump failures” declined four-fold (11% vs. 44% previously), as did the rate of alarm malfunctions (7% vs. 28% previously). The increase came in “minor defects,” which rose five-fold in the new data (43% vs. 9% previously). Median time of pump survival was similar at 27 months, the rate of malfunctions was a similar 33/100 pump years, and Medtronic and Animas were not significantly different this time. Despite the absolute increase in malfunctions, we see the results as an improvement overall, since the rate of “complete pump failures” dropped substantially. Dr. Guilhem was somewhat critical of pump manufacturers due to the very low percentage of case reports that were communicated back to the diabetes center. That led Dr. Robert Ratner to challenge industry in Q&A to improve the information flow and circle back with clinicians on the sources of pump failures.

9. Dr. Sofia Gudbjörnsdottir (University of Gothenburg, Sweden) shared insulin pump-related insights from Sweden’s impressive National Diabetes Registry. Notably, the registry includes 352,388 patients, representing more than 85% of all known people with diabetes in Sweden. Mean A1c is 8.0% in type 1, 7.8% in type 2s treated in the hospital setting, and 7.1% in type 2 patients in primary care. The number of patients at an A1c <7% is just 17% of type 1s, 29% of type 2s in the hospital setting, and 52% of type 2s in primary care. Throughout all of Sweden, 19% of patients with type 1 diabetes are on pumps, ranging from a high of 26% to a low of 10% depending on the county. Prevalence is 31% in 18-21 year olds, 25% in 22-30 year olds, and 19% in 30+ year olds. Pumps are reimbursed at 100%, but the cost is transferred to the hospital level (“people are very worried about this”). Sweden has seen a “slow increase of new pumps,” except for children where a “marked increase still is seen.” The registry is embarking on an insulin pump expansion project starting in March 2014 – HCPs will now log the pump brand, serial number, initiation date, complications, and discontinuation. This should provide some really reach data going forward.

  • Dr. Gudbjörnsdottir discussed brand new data (just in yesterday!) from an observational long-term study comparing insulin pumps to injections in type 1 diabetes. Over a mean follow-up of 5.8 years, 2,136 type 1s on pumps were compared to 13,028 on injections. The researchers used Cox regression and a propensity score to examine hard clinical outcomes. Notably, pump use was associated with a 5-6% significant reduction in coronary heart disease, cardiovascular disease, and mortality. The team adjusted for age, sex, diabetes duration, baseline A1c, systolic blood pressure, smoking, total cholesterol, BMI, history of cardiovascular disease and heart failure. We found these results encouraging, though potentially still subject to residual confounding. Nevertheless, they are certainly hypothesis-generating data. We thought her talk also provided a good example of the power of registries, and we look forward to seeing what data comes out of the insulin pump expansion project. Sigh – we continue to wish  we could see “time in zone” data although obviously six years ago, there were hardly good sensors that could reliably show time in zone.

10. Mr. Adrian Sanders, a type 1 patient, a member of British Parliament, and the Chair of the UK All Parliamentary Group on Diabetes, discussed policy efforts to put diabetes on legislators’ radars. He first highlighted The European Policy Action Network on Diabetes (ExPAND), an initiative to bring national members of parliament together to try to make a difference for diabetes patients across Europe. ExPAND has put out a toolkit made by and for parliamentarians. The idea is to provide a resource for parliaments around the world to find ready-made speeches, press releases, and other resources about diabetes. Mr. Sanders also briefly mentioned The Melbourne Forum and Declaration that took place at IDF 2013. More than 50 Parliaments committed themselves to tackling the global challenge posed by the surging worldwide diabetes pandemic – see the Declaration posted here. We were encouraged to hear about these two efforts, which are so sorely needed to share best practices across countries and raise the level of conversation about diabetes in global governments.

 

Appendix: Detailed Discussion and Commentary

Draft EASD/ADA Statement on the Evaluation of Insulin Pumps

FDA – Manufacturer And User Facility Device Experience (MAUDE) Reports On Insulin Pumps

Anne Peters, MD (USC, Los Angeles, CA)

Dr. Anne Peters gave a strong presentation on the major limitations in the FDA’s adverse event reporting system for medical devices. Following a deep dive into the MAUDE database (26,000 reports on insulin pumps in 2013 – 500 per week!), she concluded that the current data is pretty much useless in terms of understanding anything about insulin pump safety. In addition, her reading of many of the reports revealed that most adverse events actually relate to the user, not a device malfunction. Interestingly, though Medtronic has an estimated 58% share of the global insulin pump market (source cited: D-Medical’s 2012 SEC Form 6-K), Animas accounted for 81% of the 2013 FDA adverse event reports. Dr. Peters attributed the issue to “tremendous ascertainment bias,” though admitted no one on the committee really knows why Animas is so overrepresented. Taking a different tack, Dr. Peters also looked at insulin pump-related FDA recalls over the last 12 years – she only found 10 recalls, and five related to infusion sets. Dr. Peters believes the reality of insulin pump safety likely falls somewhere between 10 events and 26,000 events, though exactly where is unclear. The point of this committee, she said, is to establish what reality actually is (especially as it relates to safety) and to better inform how to use insulin pumps and diabetes technology.

  • An examination of the FDA MAUDE database revealed that 81% of the 26,000 insulin pump reports in 2013 came from Animas, followed by 10% for Roche, 6% for Insulet, and 3% for Medtronic. The data looked the same in 2012 and 2011. Dr. Peters admitted she has “no idea” why Animas is so highly represented, but it could be due to ascertainment bias. We wonder if it merely reflects J&J’s very patient-centric values and culture. Dr. Peters’ overall takeaway was refreshingly straightforward, “I cannot use this data to understand much about pump safety.”
  • In her research, Dr. Peters found that most adverse event reports are about the user; few seem to relate to a device malfunction. In reading the reports firsthand, Dr. Peters said that she often wanted to weep, especially in cases where patients died. In many cases, situations could have been avoided entirely if the patient only knew how to troubleshoot. Dr. Peters emphasized that device safety is not only about post-marketing follow-up; it’s about education and safety of use.
  • There have only been ten insulin pump-related FDA recalls in the past 12 years. Of those, five related to infusion sets.

Date

Device Type

Product

6/17/2002

Pump

Disetronic D-TRON

3/2/2004

Infusion Set

Medtronic Paradigm Quicksets

3/31/2006

Infusion Set

Disetronic Accu-Chek Infusion Set

7/13/2006

Pump Power Pack

Disetronic D-TRON

8/4/2008

Battery Cap

All Animas pumps

6/29/2009

Infusion Sets

Medtronic Paradigm Quicksets

2/24/2011

Infusion Sets

Roche Accu-Chek

1/3/2013

Pump

Animas 2020

6/17/2013

Infusion Sets

Medtronic Paradigm

1/10/2014

Cartridges

Tandem t:slim

 

Concluding Thoughts

Robert Ratner, MD (Chief Scientific and Medical Officer, American Diabetes Association, Alexandra, VA)

“EASD came to me 6-7 months ago to discuss this initiative. We were very interested in supporting this. We have clearly identified lots of limitations. All of the suggestions from the audience are heard, and we’re going to try to incorporate them. What do we need? In my mind, we need data. We need high quality data at two distinctive levels; both are necessary. First, we have the data for regulatory approval. You cannot get your device on the market without this data. We spent several hours of the morning talking about the CE Mark and the quality of the CE Mark. It’s at a higher level in US. We need to have high quality data that meets the regulatory standards in order to get a pump on the market. But that’s not sufficient. I challenge all of industry to go well beyond that regulatory requirement – to address the issue of the clinical data for true health technology assessment. That goes beyond quality control and the issues related to the device itself. Who are the appropriate populations that need to be treated? What are the true clinical risks associated with the device? It’s not just the post marketing data, where there is no denominator and no comparator. What are the true risks and benefits associated with the device? What should we be looking for on outcomes, whether they are patient reported or hard outcomes? And then you need to collect the data on cost-effectiveness.

There are several different ways of funding that – for regulatory requirements, that is the price of doing business. You must make the investment in meeting those regulatory requirements. From a marketing standpoint, there are significant potential advantages to collecting the clinical data. It puts you in a stronger marketing position. If you are able to get approval and able to sell the product, there is potential to use “coverage with evidence determination” – that could ultimately help fund the necessary studies. CMS does this for some procedures – they are willing to pay for procedure up until X number of subjects are undertaken, the data is reviewed, and a further determination can be made. That could be a tactic that device companies use - nationally or with private payers – to answer these clinically relevant questions. The other model, which is what the FDA has done with pharma, is a conditional approval. You have a new diabetes drug, but it’s only approved on the condition that you must perform a post-market cardiovascular outcomes trials. It’s a mandated clinical trial to collect the necessary data to know how to use these devices. It makes sense for the device companies to make that investment. There’s a return on development that helps companies with marketing and help providers understand how to use this.

The final goal with this project is to come out with something that is a product that will help us all grow. We want to stimulate new research, we want to develop new data that will be used in a lot of ways. I want to acknowledge the efforts of Aaron Kowalski and JDRF in designing trials and working with regulators at the FDA to develop a regulatory pathway for the artificial pancreas. By sitting down and really developing the trial design, how to collect the data, the regulatory agencies are actually looking for assistance and they are willing to listen. We can make the regulatory process a whole lot better if we can figure out what the regulators really need.

We also need to develop the data through new research that will influence clinical practice guidelines. There is very little “level A” evidence to support any of these devices. And when it does exist, it’s within a very narrow strata of patients. Provide the data and those recommendations can expand. If in Scotland, pumps are now available for all children, you can analyze the outcomes based upon the level of education patients receive. Data might show that three hours of pump education has absolutely no benefit, but 10 hours does. You then have concrete data that can go into practice recommendations that may influence reimbursement. Collect the data. Let us be an evidence driven profession; not an anecdotal data driven profession. We view this as an important first step. We’re doing pumps now. But this is technology. So we’re going through the exercise as learning experience, and then advancing to additional devices. Ultimately, we want to be ready when the data are available to make recommendations on an artificial pancreas as well. The deliverable is hopefully an online manuscript in June or July, a press conference in San Francisco in June, and a symposium in Vienna in September.”

 

Evaluation of Insulin Pumps and Sensors

Our Efforts to Provide Safe Insulin Pumps

Mark O’ Donnell (VP, Regulatory Affairs, Medtronic Diabetes, Northridge, CA)

Mr. Mark O’ Donnell provided a terrific update on what Medtronic is doing to make insulin pumps safer. His talk emphasized the need to make pumps easier to use, to involve patients earlier in the design/development process, to communicate much better with patients, and to rethink product design and risk as insulin delivery becomes more automated. Medtronic is focused on four key areas to ensure pumps are safer moving forward: modifying risk analysis procedures and increasing patient communication (e.g., notifications to customers); developing a systematic way to listen to customers (e.g., earlier involvement in product design); increasing reliability testing beyond intended use cases (e.g., water, drops); moving from passive to proactive post-market surveillance (MiniMed 530G customer outreach program). See below for more details on each.

  • Modifying risk analysis procedures and increasing patient communication. The company has created a communication matrix to guide communication decisions. For example, Medtronic recently mailed notifications to Paradigm pump users worldwide after a single pump malfunction in Australia (pressing on a disc) caused over-infusion of insulin and a severe low.
  • Developing a systematic way to listen to customers. Mr. O’Donnell boiled this down to four words: “Make the pumps easier!” The company has developed patient advisory councils to get more product input early in the design process – these include routine programs that bring patients in for human factors studies and feedback (both current customers and non-customers). We appreciated Mr. O’Donnell’s frank statement that “in the past, there was a little bit of ‘We know what patients want, let’s build it and give it to them.’ That has to end.” He said that the MiniMed 640G (“coming out in the next 12 months or so in Europe” – the F3Q14 call suggested by October 31) has a user interface that is “much easier” and was significantly altered based on patient feedback. Medtronic is also thinking a lot about alarm fatigue (“let people who use pumps customize the alarms”) and a phone controller (“a little further off for us but we’re working on that”).
  • Increasing reliability testing beyond intended use cases. Medtronic is improving pump designs to withstand water and withstand being dropped. In the past, the company relied on labeling to mitigate these risks (e.g., “Don’t get your pump wet” and “Don’t drop your pump”) – new testing will evaluate pumps in expected use conditions. Water exposure is one of the biggest concerns, and the new MiniMed 640G pump platform will have a higher level of water resistance. Medtronic is finalizing a new case design for the Paradigm and has already begun rolling out pumps with a new keypad design.
  • Moving from passive to proactive post-market surveillance. Historically, Medtronic has had a passive approach to surveillance, where the company only reacted to issues that customers raised. With the launch of the MiniMed 530G in the US, Medtronic is piloting a proactive surveillance program – every 90 days for at least the first two years on the 530G, Medtronic is contacting every user in the US. Patients are asked two very open ended questions: “Have you had any problems with the pump?” and “Have you experienced any adverse events with the pump?” Outreach efforts began in January and the results “have been very positive.” Notably, Medtronic has observed an 85% reply rate in the first 90 days of program. The company is using email, social media, websites, phone calls, letters, and even business reply cards. It’s been a “big burden” for the company to undertake this program, but information is “invaluable” and will fill some of holes in Medtronic’s post-market surveillance. If it’s successful, Medtronic will look to roll this out into other geographies. The company is looking at ways to publicly share the data from the outreach program.

Medical Devices in Europe – Regulatory issues

Key Questions

  • Has reimbursement become the new approval? This question has been emerging more and more of late. IQWiG’s Dr. Stefan Sauerland argued that as market access remains too low of a hurdle in the EU (even with the proposed changes), European countries will start to link reimbursement of new medical devices more strictly to high quality evidence. In other words, approval will be one thing, but access will be determined at the member states level with reimbursement procedures. The need to collect clinically relevant data that supports costs-effectiveness was a point also underscored by Dr. Robert Ratner later in the morning.
  • What level of evidence should be required to approve medical devices? Mr. John Brennan from Eucomed argued that a one-size-fit-all requirement for RCTs is unfair to companies, since devices vary widely and randomized controlled trials do not make sense in all circumstances (e.g., sham surgeries, minor product iterations). IQWiG’s Dr. Stefan Sauerland took an opposing view, concluding, “Hopefully we will see all these devices tested in properly designed randomized trials.” In his talk later in the morning, Dr. Robert Ratner emphasized the need for more robust clinical data on devices, with a particular emphasis on CGM and pumps (see below). There’s certainly a balance between gathering lots of pre-market data and getting devices to market in a timely fashion – where this line is drawn by regulators and companies is critical to fostering innovation, protecting patient safety, and ensuring affordable access.
  • Should medical devices be treated the same as pharmaceutical products? Dr. Sauerland largely argued that devices should be held to a similar bar as drugs, particularly with regard to RCTs. Mr. Brennan disagreed, explaining that “Our industry is not like the pharma industry” and “Devices are from Mars, drugs are Venus” (followed by a recommendation to read the first 80 pages of Dr. John Gray’s bestseller on relationships, Men are from Mars, Women are From Venus). Again, we believe this is not a black-and-white issue – devices have their own unique features that make them much different from drugs, but there is still likely a lot to be learned from the pharma world.
  • Who else should be involved in the regulatory approval process and to what extent? One of the proposed EU changes will add a specialized medical device advisory committee in the review process – Mr. Brennan worried that the committee would not be involved early enough and would be underutilized if only involved at the end of the review process. Regarding professional organizations, the European Society of Cardiology’s Dr. Alan Fraser was quite positive on their potential impact – he emphasized the importance of releasing guidance and setting standards, which is something societies can do before legislation takes effect ( “Everyone wants guidance,” he said). ESC currently has a cardiovascular device-related pilot project in collaboration with the EMA. Interestingly, Dr. Fraser was quite critical of the ISO standards, as he feels that they are mostly written by industry.
    • The perspective on patient representatives was more varied than we expected. When asked about incorporating a patient rep on the ADA/EASD Diabetes Technology Commission, Dr. Lutz Heinemann said he has “mixed feeling about it.” Given the tight timelines, he recommended giving a final draft of the report to patients for comment. ESC’s Dr. Fraser took it a step further, expressing his view that patient reps “Cannot add very much because they are not experts…I think I know more from the hundreds of patients I see than from one patient. I’m not sure if we need patients to re-duplicate all of this at another level.” While his view was certainly colored by the procedure-driven cardiology field, we were discouraged to hear this. Luckily, JDRF’s Dr. Aaron Kowalski promptly stood up and said what we were certainly thinking, “The patient perspective is very important. This is a self-managed disease 365 days per year.”
  • How will funding constraints impact regulatory reviews? Though no speaker talked much about funding, this was a clear elephant in the room throughout the day. Dr. Fraser noted that the EU Central Commission has only seven to eight full-time equivalents (!) to provide administrative support for the medical device review process. Obviously the Commission wants more support, but the political climate has resulted in all member states cutting their EU budgets. With declining industry margins, we’re not sure if or how this will be resolved.

 

--by Adam Brown and Kelly Close