The European Union is the only one – is lagging behind – where people are not protected, because the system is privatised in a way, and we don’t have standards to be sure that these private entities actually really are doing the evaluation that should be performed. In our article, we made a first proposal, a minimum minimorum, where we identified seven points where we as a European Union should be working on. Welcome to Diabetes Perspectives: Decoding the need to define minimum requirements for CGM, Welcome Tadej, I can say. Let’s start by introducing ourselves to the audience. So Tadej, who are you? I am a practising physician in the European Union that sees many people with diabetes. My initial training is paediatrics and then endocrinology in the United States. And finally, I’m also a clinical pharmacologist so that I can perform these trials to provide data that hopefully support what we do. But technology has always been very close to your heart, and you’ve been one of the key people to push use of CGM in all people living with diabetes, actually. I do believe that continuous glucose monitoring really helps both people with diabetes and us to understand how to support them in their decisions. So yes, very early on I thought that this was very important for people, and I tried to help them get it. Yeah. And so for the audience, I am Chantal Mathieu. I’m an adult endocrinologist in Leuven, Belgium, and also a day-to-day practising clinician treating people living with all forms of diabetes. And we got to know each other through many collaborations where we try to indeed use technologies in the best way in all kinds of people living with diabetes and now even early stages of diabetes even before hyperglycaemia is present. But we also have a big heart for interventions in type 1 diabetes. So hopefully in a few years we don’t have to talk about type 1 diabetes anymore. That would be nice, wouldn’t it? That would be the dream, to go towards retirement with the thought that whatever we did, the entire career actually solved. That would be almost too good to be true. Almost too good to be true. But we still have a few years, so we will manage. There is a bit of hope. There is, yes. But what is close to our hearts is the safety of people with diabetes when we propose tools to them and specifically for our glucose monitors, our CGMs. There have been some issues, for instance, in Italy and Portugal with new players coming to the market where it was unclear what the quality of the glucose sensors were. It came as a surprise to me, to be honest. I was unaware, because traditionally we only had devices that are also FDA-approved. So it didn’t really appear that we have a problem in Europe. Nobody was probably thinking about it, but then all of a sudden through the very special, and to be very politically correct I will stay with “special”, system that we have in the European Union that private entities are basically given the legal right to approve medical devices, so the “notified bodies”, and the companies simply pay for it to get the “CE mark” is obviously an issue. Yeah. There is no centralised system in the European Union that would evaluate these devices from the medical side. You introduced “CE mark”, this “Conformité Européenne” which is a mark that is given to all kinds of tools, dishwashers, different machines. When we go to our blood glucose monitors, to our insulin pumps, there is something on top: There is content quality control also happening for these: ISO marks and what have you. We do not have these measures for our CGMs. How would you see it? Right. The thing is that usually these notified bodies are legally obliged to use standards. If standards are in place, of course, this adds to the safety. We have no standard in the European Union to evaluate CGM, continuous glucose monitors. So basically when there is no standard, notified bodies can do whatever they like – have nothing to sail by. So some of them may be stringent and may be cautious because it’s patients’ lives. Some of them may simply, you know, get the money and issue the “Conformité Européenne”. So this is the real issue, not having the standard. To get a standard, unfortunately, for some reasons that perhaps many of us don’t understand, takes years. And this is also something that’s a problem. We wrote an article together pleading for minimal standards for these CGMs. But I get a lot of questions: Why is MARD alone, this mean absolute relative difference that we have in our hands, not enough? Can you explain briefly what this MARD is, and why is it not enough? This is a very good question. MARD is one of the markers of variability of data. And of course, in people without diabetes glucose is a very stable phenomenon, right? It’s almost aligned when you measure glucose continuously. And of course, the MARD for a healthy person is minimal, because basically there is no deviations from the mean. If you measure the same in a person with diabetes, there is a very pronounced variability. So the differences in between your standard measurement and the measurement you are investigating, like a CGM device, can be very large. But then if there is no standard, how to report? You may choose to report only stable areas of the comparisons that you made, and by definition you will get a beautiful MARD. So MARD mark will be very low, because it is reported only from the stable areas. And also if you report only the MARD within the normal range, of course, the variability is lower, so your MARD is lower. And you forget to say yes, but people with diabetes also have very high glucose and very low. And then, of course, the MARD is considerably higher. So the standards that are used in the United States, it is the so called iCGM, which means “interchangeable” because it goes beyond just MARD, is extremely well constructed, because it requires you to be within some boundaries in accuracy in all buckets of glucose concentration as well as during the periods when you change from, let’s say, normal to high glucose. Why? Because continuous glucose monitoring measures glucose in subcutaneous tissue. So by definition there is a delay between the blood and the subQ. When we as clinicians are pressured, like I was by our buyers, you know, the purchasers in our institutions who look for the best prices and they say, but look, this company has a perfect MARD, we as clinicians should go back and say yes, but first of all, MARD “mean” is not enough. We don’t want just a mean, we want spectrum of values. Second, we need to know how this MARD was established: the population, only type 2s, very stable, or were also people with type 1 diabetes there? The ranges of glucose, in the low, in the high, and then also, as you said, the changes. And so for once, we perhaps may have to learn, as you said, a lesson from the United States and the FDA because of this iCGM. I usually take FDA as a very serious and helpful agency. To be honest, I believe they did a lot of good things already, and I’m not ashamed to learn from them. But then we can also learn from our British colleagues, because the British diabetologists did exactly this. They advised the regulator that it’s dangerous, unless we know this data. And they simply banned devices that do not meet the iCGM standard in the United Kingdom. So finally, it looks like that the European Union is the only one – lagging behind – where people are not protected, because the system is privatised in a way, and we don’t have standards to be sure that these private entities actually really are doing the evaluation that should be performed. In our article, we made a first proposal, a minimum minimorum where we identified seven points where we as a European Union should be working on. Specific things were proposed, like testing the sensor in a range of populations enriched for people with type 1 diabetes, in a range of glucoses with minimally having a certain percent of measures happening in the very low space, a certain percentage of measurements happening in a very high space. But we also said that if the manufacturer knows specific weaknesses of their product, it’s fine, as long as they report it, as long as they inform clinicians. What kind of weaknesses, for instance, should they be reporting? Well, what the iCGM standard also requires is that all this is performed throughout the sensor’s declared lifetime. So the sensor that is declared for 15 days may in reality only work ten, and then, you know, the lagging starts. So they have to show that the quality is consistent day-to-day, and also that you take a batch from here and a batch from there and they’re comparable. So that they don’t produce a super good batch for testing. And then those that go to the market actually do not match the same. So, controlling devices is a complex process that has to be continuous. And interestingly enough, there is legislation in the European Union that requires this, almost a brand new one, but there are no standards, and still there is no medical body like EMA for medicines that would finally evaluate the medical part of the device and say yes. So this is why we believe that we should have, after the materials and radio frequencies and everything was evaluated by notified bodies, we should have a general agency, probably part of EMA, that would finally say: This device is not only safe with materials, construction, and is compliant, because “Conformité Européenne” means it complies to the technical requirement, which is important and should be continued. But in the end, probably an agency like EMA, I thought, should have a branch for technology that would evaluate medical data and says: Yes, it was tested in all populations. It was tested in all age groups, in all situations. It does bring benefit, and it is safe, it is not dangerous. So it looks like a two-step approach where, first of all, you can put the tick that we have now with the CE, namely the plastic is not toxic, the little measuring rod doesn’t fall off, all these things, the glue is not toxic, check, check, check. But then the clinical evaluation, so that we clinicians and the people using these sensors can be reassured. But other things that we would also like to see reported, for instance, is how stable is this sensor on different parts of the body. And again, it’s not a shame if it’s only on the arm, but report it. Exactly. Same with interfering substances on the measurements. Not a shame that there’s interference, but report it. Let us know. This is the kind of normal communication between a product and a clinician. So if we know we can prevent, we can educate people on how to use it. And, you know, tell them, look in this part, it’s less safe than in other parts. And it makes perfect sense. But not knowing basically really is dangerous. It’s dangerous, and it basically increases anxiety in people, which is even worse, because then they will not use it. Exactly. If they don’t use it, they lose metabolic control and all these terrible consequences, late complications are again closer. We thought we got rid of them. And all of a sudden, with the mess that we have in the European Union with these devices, it may backlash. Because it’s a little bit different even than a pacemaker. It’s not only a communication from manufacturers to clinicians who need to know how trustworthy is this tool, but there’s a third, even more important player, the person using this tool. Because more and more, we as clinicians but also the people using these tools trust these tools blindly to adapt their insulin dose. Exactly. And for good reason, because we only had concomitantly FDA-approved devices in Europe. So not knowing that basically they did comply with standards, because they had to comply for the United States, we were safe. And now all of a sudden, when this is circumvent and companies come only to Europe, specifically to the European Union I should say, where there is a mess, so they can come with whatever. And they cannot come with this to the United States. We are kind of a cheap market. A third world market all of a sudden that is not regulated, which really is difficult to understand for the European Union. So a very, very important topic that, you know, even backlashes when we think of therapeutic inertia, in titrating our treatments. And it’s offensive because people will think, look, I mean, this is what European Union does. They don’t care for us. So it’s very difficult. And I believe, we should notify the European Commission and the European Parliament that people are in danger. So we’re coming to my next question: What should we do next? I mean, we have united in Europe with learned societies, with patients, with people living with diabetes, all together in European Diabetes Forum, IDF Europe. What can we do? What should we do? I think together with these learned societies that are more technical, like the one that basically suggests to ISO which standards should be used from the technical side, we should probably produce a white paper that’s not too long on what we believe is imminently necessary to be a standard for evaluating CGM. And then probably, we should use all influence that we can, not only perhaps just from people with diabetes and their associations and the learned societies like diabetology groups but probably also from the honest part of industry. Absolutely. They should say, look, I mean, you know, we invest in safety, everybody should, to protect people and go together to the legislature, which in our case is the Parliament and to the European Commission, who has a decisive power to protect people when necessary. So we as societies together with industry and in Europe we do have MedTech, where you have a gathering of industry. We can build on the paper we have written where already a suggestion was made, go to the policymakers and demand for the safety of our patients that they should be taken care of. I think so. It’s very important, because then we did our job also as clinicians. I mean, it is our business to tell politicians when people are in danger because of an omission that was not identified prior, because were relying on a very good agency like the FDA. But now when this discrepancy is obvious, I think perhaps it’s an opportunity that Europe also changes a little bit, and that the EMA does get a branch for technology and then pacemakers will not be CE marked by the same notified body as their hair dryer. So let’s look into the future, because we are living in exciting times, Tadej, when you look at everything coming towards us. These CGMs having a longer life. We see products coming with really top performance, being connected to pumps, algorithms, etc., measuring multiple metabolites now. So I believe the future is bright, and it’s very close to your heart, the fact that not only the typical person with type 1 diabetes is using these tools but also people with type 2 diabetes with insulin. But also those without insulin can benefit from these tools. And now extending it to pre-diabetes in type 2 and to early-stage diabetes in type 1. So an amazing expansion of the application of these tools. I believe that, you know, when we started our careers, type 1 was very difficult to manage and type 2 was impossible. Now all of a sudden, type 2 with modern medications and with a pipeline that, you know, is in waiting, it’s a disease that’s preventable even, not just treatable, and so seems to be type 1. So I do believe that this CGM, continuous glucose monitoring, will mostly be for identifying the trouble and preventing it. So this is the dream I have. So that this is not used like now companies have, you know, disease modifying medications, but they say, but you need heart failure to get it, knowing that we can prevent this heart failure, right? So this is my dream that really CGMs will be used for identification of glucose variability, and this variability will be treated, so that we can prevent hopefully, you know, stage three type 1 diabetes, or overt type 1 . Perhaps it will be something that we won’t see anymore. No ketoacidosis, not these terrible complications. And I do think now already, it is possible to prevent type 2 diabetes. And if you prevent type 2, you prevent all the complications of type 2. So I think, you know, even the legislators and payers should be super interested in this, because the big money actually is in complications. But so exciting times, where we have also AI coming into the picture, really pointing us the way. But we need safety, we need reliable sensors. We need structure to be sure it’s safe. Otherwise we are deceiving people in the European Union, and this is our task, so the task of clinicians to say, look, something went wrong, let’s fix it. Excellent. Thank you so much for this conversation, Tadej. Thank you, it was a real pleasure.