Conference Report (Part I)


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Conference Report (Part I)

  1. 1. Conference Report (Part I) Towards An Artificial Pancreas: An FDA-NIH-JDRF Workshop Lister Hill Auditorium, National Institutes of Health, Bethesda MD July 21-22, 2008 On July 21 and 22, 2008, the Food and Drug Administration (FDA), in collaboration with the National Institutes of Health (NIH) and the Juvenile Diabetes Research Foundation (JDRF), held a public workshop on the state of the art in the research and development of an artificial pancreas. “Towards an Artificial Pancreas: An FDA-NIH-JDRF Workshop” provided an opportunity to discuss the progress and remaining challenges in the development of closed-loop systems designed to regulate glycemic control in people with diabetes. In attendance were research scientists, clinical investigators, experts from industry and government, JDRF staff and volunteers, as well as patients and their families. The overall goal of the Workshop was to accelerate the development of an artificial pancreas, or closed-loop system, for the treatment of diabetes mellitus. The workshop featured a tight schedule of presentations by world-renowned experts in type 1 diabetes and other disciplines, with each of the six sessions followed by roundtable discussions. Included were talks on the design of closed-loop control systems, the results of recent clinical trials, how to define success and failure of a closed-loop system, algorithms and in silico (computer-based) models, engineering challenges, advancements in in-hospital glycemic control, and patient considerations. This report provides a broad overview of the workshop, highlighting recent achievements in the development of an artificial pancreas, immediate and long-term goals, and key issues that emerged from the meeting. A more comprehensive summary (Part II) will be available within the next few weeks. Opening Remarks Highlight Recent Progress, Importance of Continued Collaboration Janet Woodcock, MD, Deputy Commissioner and Chief Medical Officer at the FDA, opened the conference with a discussion of the challenges in turning innovations in basic science and technology into safe and effective treatments for patients, specifying how this “translational block” was the impetus for the FDA’s Critical Path Initiative. Dr. Woodcock described the initiative as not just an FDA project, but a “call upon the scientific community to band together to find new ways of advancing the development of innovative science on the critical path to becoming actual products.” In the context of the artificial pancreas, which the FDA has made one of its highest-priority Critical Path Initiatives, she detailed some remaining challenges: • Advancing the science of biomarkers in humans. We have good biomarkers in the diabetes field, she explained, but “they don’t serve us well enough for this particular project, because there are more things we need to know about the dynamics of blood sugar.” • Establishing the best possible clinical trial design and endpoints. How do we evaluate the performance of these new technologies? Though we all want them to get to patients, we want them to be effective and to perform well. • Addressing informatics barriers. • Translating emerging performance standards into regulatory standards, “so that we’re all on the same page about what needs to be done before FDA approval and commercial marketing.” • Developing new paradigms for working together. She described the FDA’s successful partnership with JDRF’s Artificial Pancreas Project as a prototype of “what we need to do in so many areas.” Dr. Woodcock described a strong collaborative relationship among the FDA, NIH, JDRF, and the Diabetes Technology Society, and outlined the broad goals that each have in mind: in the short-term, to
  2. 2. accelerate the development of closed-loop technologies that will bring real change to patient management of their diabetes; and in the long-term, to find a cure for diabetes and its complications. Griffin Rodgers, MD, Director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the NIH, focused his introductory remarks on the “truly impressive” progress that has been made in the artificial pancreas field to date. He identified inter-agency collaboration as the catalyst for this success and highlighted several important achievements: • Shortly after the December 2005 meeting Obstacles and Opportunities On the Road To an Artificial Pancreas, the FDA’s decision to make the development of the artificial pancreas one of its Critical Path initiatives. • In the last three years, the approval of three new real-time continuous glucose monitor (CGM) systems, including a pediatric model that reports glucose values continuously for up to seven days and detects trends and tracking patterns; and an integrated CGM and insulin pump. These devices, he emphasized, have not only helped us to understand the complex regulation of blood glucose and the pathophysiology of hypoglycemia, but they have provided a basis to build upon and reach the “long sought after” goal of developing an artificial pancreas. • NIDDK partnerships with the National Institute of Child Health and Human Development (NICHD) and the Diabetes Research in Children Network (DirecNet) are uncovering the role of technical advances in the management of type 1 diabetes in children and adolescents. • Collaborations with the National Institute of Biomedical Imaging and Bioengineering and the National Center for Research Resources are supporting innovative research and the development of new and low- cost technologies that may be applicable to the field. • The development of new networks, particularly by the JDRF, which has helped to establish further progress towards establishing closed-loop devices. • As a result of the Critical Path initiative, the formation of a Health and Human Services Interagency Artificial Pancreas Working Group, which “has catalyzed activity in the field and has organized the current workshop.” • The development of a recently released draft guidance, Developing Drugs and Important Biologics for the Treatment and Prevention of Diabetes. The report has been positively received in the diabetes community, Dr. Rodgers said, and has had important implications for NIDDK-supported clinical trials. • The launch of JDRF’s Artificial Pancreas Project, which includes a multi-center clinical assessment of continuous glucose sensor use and a 7-site international consortium of researchers developing and testing early hospital-based versions of an artificial pancreas. Since December 2005, NIDDK has supported cutting edge research for the development of a minimally invasive glucose monitors, long-term implantable glucose monitors, new glucose-regulated insulin-delivery technologies, technologies to increase the biocompatibility of the devices, and the development of algorithms that may mimic physiologic homeostasis. All of these technologies, Dr. Rodgers said, will “eventually be components of a future artificial pancreas able to lighten the heavy burden of diabetes self-management, alleviate hypoglycemia, and reduce complications by making good control exceedingly more possible.” He anticipates further accelerated activity in the upcoming year, driven in large part by the energy and synergy of the 2008 workshop. Larry Soler, Vice President of Government Relations at JDRF, emphasized what ultimately became one of the overriding sentiments at the meeting: that the core technologies necessary to develop a safe and effective artificial pancreas—the glucose sensor, the insulin pump, and the algorithms—are now available, and that it is going to take “all of us working together” to address the remaining hurdles and make a difference for people with diabetes. Mr. Soler reiterated the importance of Congress’ decision to commit an additional $300 million for type 1 diabetes in moving progress along in a number of avenues. He also reminded participants about why an artificial pancreas is desperately needed for type 1 patients: On the same day that Congress approved the Special Diabetes Funding, he received the sad news that a
  3. 3. former JDRF intern had died from complications of diabetes. Extensive evidence shows that better glucose control prevents diabetes complications, yet most type 1 patients are not achieving the recommended targets. Continuous glucose monitoring shows promise in addressing this problem, Mr. Soler said, but not all patients respond to CGM data, and even model patients can’t respond 24/7. “The bottom line,” Mr. Soler said, “is that too many people with diabetes are not doing well enough. The current standard of care for people with diabetes, and their health outcome, is simply not acceptable. We need to get to a point where there’s some help in making decisions that are safe and effective, and we believe that’s going to be in an artificial pancreas.” Mr. Soler also noted that while there is excitement about where the science is heading, there is concern about where the commercialization of a closed-loop system is today. To bring the artificial pancreas to patients faster, JDRF is focused on several goals: • Accelerating the availability of a first-generation artificial pancreas. • Ensuring the artificial pancreas and its components are widely available. • Ensuring devices from multiple companies are approved and reimbursed. • Encouraging investment in next-generation technologies. In FY08, JDRF funded $165 million in research towards a cure for type 1 diabetes, and in FY09, expects to fund almost $200 million, making JDRF not only the world’s largest charitable funder of type 1 diabetes research, but also the largest charitable funder of research in any disease category. In her welcome at the start of the conference’s second day, Judith Fradkin, MD, Director of the Division of Diabetes, Endocrinology, and Metabolic Diseases at the NIH, described an “exciting first day” that brought much progress towards (1) elucidating important clinical outcomes that the FDA might consider for approval, and also additional studies going forward; (2) outlining a plan to move from some of the early human studies in carefully controlled settings to real-life trials; (3) and defining some analytic approaches to improve algorithms based on data that has been collected through these studies. She reminded everyone about the recent extension, through to 2011, of the Special Type 1 Diabetes Research Fund, and she encouraged attendees to think about and contact her directly ( with their ideas about the kinds of research that the NIH should try to stimulate to ensure progress in this area. Meeting Highlights From the presentations, a few essential themes emerged: • The current standard of care for patients with insulin dependent diabetes continues to be insufficient. Diabetes is a leading cause of heart attacks, strokes, amputations, blindness, and kidney failure; and as a result, medical costs for people with diabetes are as much as five times higher than for those without the disease. An artificial pancreas, by improving glycemic control, could ameliorate the high morbidity and mortality associated with type 1 diabetes. • Researchers are optimistic that a commercially available first-generation artificial pancreas is “around-the-corner.” However, it will likely be a hybrid or open-loop system rather than a fully closed- loop device. Achievement of this milestone will be credited to advancements in science and technology, together with the development of close collaborations among the FDA, NIH, JDRF, and other agencies. Regarding the form that an eventual artificial pancreas might take, or the capabilities it could have, several participants reiterated the importance of not making perfection the enemy of the good. • Technical challenges remain. Several recent closed-loop studies, in children, adults, animals, and in silico, support the benefits of the artificial pancreas in regulating blood glucose levels. Researchers will need to continue to focus their efforts on improving sensor performance and on fine-tuning the systems, particularly the algorithms. Areas where more work is required include improving control after meals, during and after exercise, and when individuals are under stress. • Collaboration and teamwork are key to continued progress and were deemed essential “to bringing the artificial pancreas to fruition.”
  4. 4. Key Discussion Points and Issues By Session I. State of the Art: Designs and Results from the Latest Closed-Loop Studies Moderator: William Tamborlane, MD. Yale University, New Haven, Connecticut. Recent closed-loop studies have shown measurable progress and positive outcomes. They include studies on the prevention of hypoglycemia with automated pump shut-off, closed-loop studies in children and adults, closed-loop studies using both insulin and glucagon, and in silico study designs, such as subcutaneous model-predictive closed-loop control. Comments made during the roundtable discussion focused on: • The need to increase the pace of inpatient feasibility studies that will pave the way to future outpatient studies. • Challenges associated with realizing the full effects of insulin after turning off basal delivery. • Difficulties in controlling meal excursions, particularly after breakfast. • Challenges related to the physiological effects of exercise. • The question of whether or not to include glucagon in an artificial pancreas; there was some consensus that in early trials it may be best “to keep things simple,” though it may ultimately be valuable for those with severe hypoglycemia. • Not getting too attached to any one algorithm or closed-loop model; and • Not slowing progress towards the availability of an artificial pancreas by “shooting for perfection.” II. Defining Success and Failure: Appropriate Measures Moderator: Boris P. Kovatchev, Ph.D., University of Virginia, Charlottesville. In this session, presenters discussed trial design in the development of an artificial pancreas, clinical and statistical outcome metrics, and the measurement and quantification of hypoglycemia. The traditional measure of glycemic control, hemoglobin A1C, was acknowledged to be a poor measure of closed-loop system performance, and other tools, such as mean glucose concentration, time within target range, hypoglycemic episodes, and risk analysis including low and high blood glucose indices were identified as more appropriate. Clinical trial designs were discussed, and the importance of having a staged approach to evaluating closed-loop systems and incorporating frequent blood glucose measurements during early studies were stressed. Early feasibility studies should focus on patient safety. A lively discussion followed this session, with the following issues raised: • There is a strong need for a controlled trial showing that patients can experience reduced rates and a lesser degree of hypoglycemia using a closed-loop device; it is unrealistic to think that any such device can avoid hypoglycemia altogether, at least not at this point. • Restoration of hypoglycemic awareness is an important aspect of reducing hypoglycemic episodes. • Symptomatic hypoglycemia may be an important end-point measure, although non-quantitative assessments present further challenges. III. Algorithms: State of the Art and Future Directions Moderator: Roman Hovorka, Ph.D., University of Cambridge, United Kingdom. Session 3 focused on current algorithmic approaches and in silico models, the critical question being, Do we trust simulator validity? The roundtable discussion following this session was again lively, with the panelists receiving a flurry of challenging questions. Key issues raised included: • The need to develop uniform criteria in order to effectively compare various models, including open- versus closed-loop systems. • The fact that current sensors have not been approved for therapeutic changes, and that they measure interstitial fluid glucose, not blood glucose. • What constitutes an Investigational Device Exemption. • Algorithms may need to be customized to each patient to optimize their performance. • The importance of testing in silico models under extreme conditions. • How simulator outcomes compare (or will compare) with data from artificial pancreas trials in real
  5. 5. patients. While there was strong consensus on the value of in silico testing, especially its efficiency and elimination of the need for animal trials, some participants pointed out the simulator is but one tool, and thus not the only option for testing the safety and efficacy of artificial pancreas systems. Human trials, some argued, are the only way to know for sure whether an algorithm works. IV. Engineering and Patient Considerations When Building a Closed-Loop System Moderator: Kelly Close, M.B.A., Close Concerns, Inc., San Francisco, California. Session 4 featured a presentation on the behavioral aspects of building a closed-loop system and highlighted the importance of reducing the treatment burden on patients, especially children. Some users, it was discussed, are discontinuing their use of CGMs because they are overwhelmed by the information provided. Following this presentation and closing the end of the first day was a roundtable discussion that included industry leaders, a parent of a child with diabetes, and an adult with diabetes. Key discussion points included: • Echoing comments made earlier in the day, panelists were in general agreement that “zero hypoglycemia” should not be a requirement for a closed-loop system. • The need for both parents and children to share the responsibility of a closed-loop system. • How to quantify risk to patients is a pressing challenge. • According to information collected by one of the panelists, patients are most wanting of two things from an artificial pancreas: First, the control of hypoglycemia without undue risks; and second, improved quality of life. • Patients want to be able to over-ride the device. • An argument was made that the first artificial pancreas might best be a hybrid system characterized by automatic basal insulin control (to address hyperglycemia aggressively), but with a more conservative set point for hypoglycemia. • Safety, as mediated by the algorithms—not control—was felt by some to be the foremost challenge to meet in order to bring us closer to full-scale clinical trials. • Recommendations varied on where and in whom to conduct the first clinical trials, but most agreed on an adult population. Adults have a lower risk profile and Institutional Review Board issues will likely be less complex. V. From Automated Insulin Delivery to an Artificial Pancreas: How We Get There Moderator: Aaron J. Kowalski, Ph.D., Juvenile Diabetes Research Foundation, New York, New York. The first session on day two centered on how to move from automated insulin delivery to a realized closed-loop system. Presentations focused on the effect of exercise on counter-regulatory responses to hypoglycemia, lessons learned and future opportunities for an implantable closed-loop, closed-loop use in early onset diabetes, and biomechanical approaches to curing diabetes. A three-step strategy for “how we get there” was described. Step 1: We need to be able to turn the device off. Step 2: The availability of a closed-loop system needs to happen soon, and will require commitment from all stakeholders. Step 3: The device needs to offer fully automated insulin delivery. Points from the roundtable discussion were led by the question, What is the future? • There is room for a faster-acting insulin. • There is a better chance to get to euglycemia if latency (a sensor problem) can be addressed. • Delay in the delivery of insulin was identified as the weakest point in the system. • To address variability and fluctuations in glucose levels, especially in children, different algorithms may be required for different patient populations. Algorithm fine-tuning, rather than restructuring, was the predominant recommendation. • Many researchers believe that combining closed-loop therapy with islet cell transplants provides significant benefits to the patient. VI. Beyond Insulin Dependent Diabetes
  6. 6. Moderator: David D. Klonoff, M.D., University of California San Francisco, Mills-Peninsula Health Services, San Mateo, California. The final session included presentations on novel tools to measure metabolites in hospital-based studies, the Department of Defense’s Metabolic Monitoring Program, the application of physiologic models to artificial pancreas research, closed-loop insulin infusion for critically ill patients, and biofouling, which refers to sensor failure caused by the molecular and biological events taking place at the sensor’s surface. Comments at this final roundtable discussion were directed to the questions, What are the practical barriers to developing an artificial pancreas, and what type of solution would you recommend? • Issues of electromagnetic interference and connectivity of hardware components must be addressed. • Most panelists cited the sensors as being the most problematic component in the systems being developed, with agreement that sensor improvements will be needed to achieve a totally closed-loop system. • One participant felt that the existing technologies for developing a simple artificial pancreas, such as automatic suspension of basal insulin delivery, already exist. He added that there were essentially no risks to this model. • Controllers for currently available continuous sensors are inadequate. • In-hospital study results are promising, many of which use blood glucose measurements. • No chronic-use sensors are available, in part because of the difficulties involved with tissue dynamics. Considerable efforts are under way to develop a coating for sensors that will allow them to “survive” biofouling and be used effectively for longer periods of time. Examples included fibronectin gradients, VEGF, and implant texturing, which decreases micro-vessel density. • The conference ended with a discussion of whether some of the parameters for evaluating efficacy, such as normal blood glucose targets, are creating expectations that are beyond reach.