Without question, one of the most anticipated devices in the diabetes world is an artificial pancreas. Bill and Anna’s day-to-day reporting on their experience with the bionic pancreas trial is still widely read on Glu. Still, it’s one project of many being developed around the world. Some are a dual-hormone system of insulin and glucagon, others use insulin only, with a view to incorporating a dual-hormone system in the future. We contacted Aaron Kowalski, Vice President of Artificial Pancreas, who leads JDRF’s Artificial Pancreas Project, and had an in-depth conversation about the origins of the Artificial Pancreas Project and how it has evolved since its inception in 2005, shortly after he began working for the organization.
Dr. Kowalski, who was diagnosed with type 1 diabetes at the age of 13 in 1984, has been deeply invested in diabetes research for years, and is a well-known speaker at conferences around the world and has published numerous articles, including an article he co-authored about the effectiveness of continuous glucose monitors (CGM) in the New England Journal of Medicine.
How It Began
The story of the artificial pancreas (AP) actually begins with the CGM. When we asked how the Artificial Pancreas Project started, Dr. Kowalski talked about his efforts to bring technology more into focus at JDRF. Ten years ago, he was working with the Diabetes Research in Children Network (DirecNet) at NIH on a CGM study, specifically looking at Abbott’s Navigator, which was an amazing eye-opener for people involved in the project. “The CGM completed a puzzle piece that was missing in order to go after an artificial pancreas. If you had this continuous information, and we have the pump, we should make try and make a real push for an artificial pancreas, with the CGM being a near-term solution,” he said. A challenge at the time was that payors were not covering CGMs and doctors were not prescribing them. The first hurdle was to gain acceptance for the CGM to pave the way for the artificial pancreas.
The AP Project launched in 2006. One track focused on the CGM, and the resulting data had a powerful impact. JDRF’s study changed the healthcare industry’s view of the device. “The great news after the trial the JDRF funded is that payors started covering the devices and it really opened up the business model for the artificial pancreas,” Dr. Kowalski said.
A second track of the AP Project looked at Medtronic’s work in creating a closed loop system in conjunction with a study on hypoglycemia JDRF funded at Yale. They saw a need to expand the scope of the project. In 2006, JDRF funded five groups, four in the US and one international, to combine the expertise of engineers and doctors to get their input on how a closed loop system would safely function. While the data looked promising, a question remained: “Can we fully close the loop?” The industry wasn’t moving ahead with devices because there were concerns about the accuracy of CGM readings and sensors failing, causing an overdose of insulin.
During the JDRF CGM trial, Aaron was on the operating committee of the trial with Dr. Roy Beck (JAEB Center for Health Research and T1D Exchange), Dr. Lori Laffel (Joslin Diabetes Center and Harvard Medical School), and Dr. William Tamborlane (Yale Center for Clinical Investigation and the Diabetes Research Center). The data from the trial showed that a person with type 1 diabetes with an A1c of 7.8 (the average A1c for a child entering the study) spent more than twelve hours a day with blood sugar levels above 180, and over an hour a day below 70. These data suggested that even an “imperfect” system could have a great benefit. That is, the first artificial pancreas systems didn’t necessarily need to restore normal blood sugar levels if that caused an increase in the risk of going low. But, instead, if a system reduced some of this time spent high and low and was very safe, that could be great. The next step was to measure how often the sensor gave a reading that was higher than the actual blood sugar level. With that information, they could set a limit to ensure safety in a semi-automated system.
A six-step plan outlined the path to a fully automated artificial pancreas was developed by JDRF. Each step took particular measures into account to allow for adjustments—being able to shut off the pump, or change incremental doses of insulin, depending on individual needs. JDRF’s strategy was to fund each aspect to gather as much data as possible. A number of projects were funded, including Dr. Ed Damiano’s dual-hormone bionic pancreas system. The industry was quick to embrace the six-step roadmap, and progress has been made ever since, but not without challenges from regulatory organizations.
Working with the FDA
Medtronic’s 530G Enlite Sensor has been an important step on the path to the goal of an artificial pancreas system. Convincing the FDA to approve it was an incredible challenge with heated discussions, and advocates for diabetes research played a significant role at the hearings about the device. Dr. Kowalski’s passion for getting this device to market was personal. His brother, who also has type 1 and was diagnosed at age three, had a history of severe hypoglycemia unawareness. “Diabetes played a big role in our house, and this was in the early 1980s, before finger testing was available. I can’t tell you how many ambulances we had to call. And my parents were super engaged, smart, and dedicated to our diabetes,” he said. “So low blood sugar and threshold suspend made perfect sense to me.”
The FDA’s primary concern was the accuracy of the sensor, and the possibility of DKA events. Dr. Tamborlane from Yale demonstrated that hypoglycemia was the larger worry over high blood sugar levels. Because the similar concerns came up with the development of the insulin pump, data showed the rate of ketones developing with high blood sugars when the pump was turned off were relatively slow, and that serious risks were significantly lower compared to the dangers of lows. This meant that turning the pump off for a maximum of two hours would be safe and could reduce low blood sugar exposure.
The solution came when FDA asked for guidance. A coalition led by the JDRF and including endocrinologists and other doctors representing the American Diabetes Association, the Endocrine Society, and other stakeholders were asked to define “a reasonable pathway to not only get predictive and threshold suspend systems out there, but all the way to dosing of insulin.” As a result of these persistent efforts to get the FDA to understand the benefits, the current working relationship is much more effective. “People need to have the tools to be smart about their diabetes care,” Aaron said. “We had the data to help educate the FDA, since this was such a totally new, out-of-the box thing.”
When asked what the biggest obstacles are in getting new devices to market and how people in the diabetes community can help, Dr. Kowalski felt the insulin-alone hybrid systems have the best chance to getting to market first. While people will still have to bolus for meals, the system will pick up the slack and bring levels into target range. Medtronic’s 670G is a forerunner in the race to get a hybrid system to market soon. “What’s interesting for me is that my top priority at the JDRF is trying to drive this out to people. I think the studies are great, but until I benefit from it, my brother benefits from it, until you guys benefit from it, it doesn’t mean a lot. We haven’t brought it home.” It’s more than having a sensor-augmented pump. The Helmsley Charitable Trust is working with Medtronic and JDRF on a $17 million project to build a highly accurate sensor.
How Research Shapes Innovation
This innovation has motivated other companies to pursue similar projects. “Other companies are rapidly trying to be in the [hybrid system] game as well because it works, it’s very safe, it’s very effective, and I don’t think you can be competitive if you don’t do it. Two years ago I don’t think the companies were sure of about that, but the trials are happening now and it is completely real for them.”
Medtronic’s 640G will be released in Europe soon. It has made significant improvements in eliminating overnight lows. On the other hand, dual-hormone systems are being developed by a number of groups. Important questions remain on the table about the how to safely use glucagon in a closed-loop system. For example, ensuring when glucagon is not available in the system (i.e. a set occlusion/failure) that the system can detect this and there is not too much insulin on board. “Glucagon adds a layer of complexity,” he said. “In the bionic pancreas trial, the average dose of glucagon was 800 micrograms a day. What is the implication of adding 800 micrograms of glucagon a day if a person, who at times, already may be hyper-glucagonemic? (i.e., producing too much glucagon—Ed.) People with type 1 still make glucagon, and in fact, excessive amounts of glucagon, often post-meal.”
He does support the idea of the dual hormone system for the long-term. “Though the approach on and the effects of glucagon remain a question mark, that’s not to say I don’t think it’s important. JDRF supports Tandem’s creation of a dual-chamber pump, and is funding Xeris in development of stable glucagon for use in future dual-hormone systems, among a number projects.” The concern, however, lies in the process the system faces in getting approval, and that by saying it will be available in 2017 may be setting expectations too high.
When asked why it’s essential to fund more than one project at a time, Dr. Kowalski said, “That question is actually the answer to the question how we will get to a cure in my mind. Ultimately what drives progress here is competition. If you look at the Medtronic sensor…their sensors that launched in 2004 was the same sensor that they used for their CGMS system. The doctor version was built in 1999. And really that was the same sensor that came onto the market until Abbott and Dexcom came along. And I give Dexcom a tremendous amount of credit here because that competition helped the entire field. Medtronic has really upped their game and will have a tremendously better sensor because Dexcom is pushing them.”
Abbott’s new FreeStyle Libre Flash system is particularly exciting as he looks at what devices are coming out as a result of a more open market. “That’s going to launch, with a two-week sensor wear, and zero finger sticking. That is amazing, how awesome is that? The system is much smaller than the other CGM systems out there. It’s not real time, but for many people that is going to a huge improvement in their lives.”
“I get asked all the time if there will be a cure in our lifetime. Some people believe that the companies have no motivation to get to a cure because they sell us a lot of this stuff. Ultimately these companies are trying to figure out is what’s next. And the competition drives that. So regardless of which system we’re talking about specifically, keeping these companies moving is a very good thing for us.” He compared producing these devices to smartphones. “There was a time when everyone had a BlackBerry, but now, unless you’re on Wall Street, there are far fewer people using them. It’s a perfect example of not iterating and getting new things out there faster. Competition drives innovation. And from a JDRF perspective we want multiple options because this is good for people.”
People frequently ask why JDRF funds so large companies like Medtronic and J&J. “Type 1 diabetes is a small market size for companies to sell things to, versus cancer or other disease states, where there are a lot more people affected. So then you get into resources, how many resources are there to drive things forward? Most people don’t appreciate that Medtronic is the only pump company—the only one—that currently makes a profit. Think about the implications of that. So when we ask companies to move faster or take on something they are not planning on doing, this can be a very, very difficult to do – particularly when other projects are competing for resources.”
“The research side of JDRF is obviously our core strength,” he continued, “but the ultimate benefit is people with diabetes doing better. Until we have people with diabetes doing better, we haven’t succeeded. If we can help drive companies to deliver better solutions sooner, we think that is worth the investment.”
With an abundance of opportunities to fund, JDRF devised a strategy to help as many projects along as it can. After the initial phase of research was completed for Dr. Ed Damiano’s bionic pancreas study, it was able to be transitioned to the NIH’s special diabetes program for additional funding. JDRF communicates frequently with the Helmsley Charitable Trust (HCT)—JDRF’s most important partner, the largest private funder of type 1 diabetes research (and founding sponsor of T1D Exchange). JDRF and HCT seek to obtain enough data in developing new products to de-risk them enough so that other organizations such as the NIH, which has a much larger biggest budget, will take these projects on and help see them to completion. JDRF has enough money to do the research and gather the data, but launching a new device on the market is much more expensive. For example, Afreeza’s inhaled insulin took over a billion dollars to bring it to market, and JDRF can help by funding such products to a certain point. With the initial research complete, it makes these organizations eligible for larger grants, such as the ones from NIH. Ultimately, this gives JDRF the ability to take on high-risk ideas that help fuel their research arm. “We want to have the biggest impact with our dollars and not just fund things for the sake of saying that we’re funding them,” said Dr. Kowalski.
The Role of Advocacy
“This is all about advocacy,” Dr. Kowalski said. “We can teach people about the process of research and bringing products to market, and it’s important to understand how easy it is to send an email to let your representatives know what needs to be done. It pays huge dividends.”
When people who give money to nonprofits like JDRF express their concerns about how the money is used, Dr. Kowalski explains the profit from these projects is funneled back into research. When products are successful, JDRF recoups its investment with a bit of interest, and, “It goes right back into the next generation of products that we think will be meaningful to you,” he said. And sometimes, people wonder whether this means JDRF has given up on a cure. “Of course, the definition of a cure is debatable, be it islet transplants or pancreas transplants—regardless of how you define it, a cure where you can just walk away going to take much more work. We’re focusing on the long-term goal of having a cure, but we need to fund solutions in the meantime—making infusion sets better, and the overall strategy is still there. What we’re focused on being as impactful as possible, as soon as possible, and as efficient as possible.”
As someone with type 1, his own routine includes an Animus pump and has used a Dexcom CGM every day since 2006. How often does he change his lancet? “Very infrequently. The last one was changed months ago.” He relates to all the commentary he sees every day on Glu. “When we talk about type 1, we say this is a club no one wants to join, but there are so many amazing people in this club.”
How You Can Help
In making sure the road to the artificial pancreas is open, he said, we as a community need to support current efforts to get Medicare to cover CGMs. This is a big priority for JDRF at the moment. Signing petitions and contacting representatives can help, and you can visit jdrf.org/action to learn more. Data from T1D Exchange has shown elderly people are at the most risk for hypoglycemia, and the artificial pancreas system will be the next fight. “Everyone needs to be a strong diabetes advocate, and that will help us turn the tide.”