Regulatory Science Virtual Symposium: “Clinical Research Career Pathways” Session 2: From Academics to Industry – A Physician Researcher Perspective (2021)

1. Artificial Pancreas Device System (Closed System)
1. Can connected devices and an algorithm better regulate insulin delivery matched to glucose levels than patients/clinicians?
2. What would need to be done for patient/clinician acceptance?
3. What would be the regulatory pathway to a commercial device?
2. The need for the artificial pancreas
1. HbA1c goal is to have it before 7.5 for children, and below 7 for adults
2. Data shown in data exchange indicated that children and adults do poorly in managing diabetes on their own
1. Technology helps; mean value HbA1c is lower in insulin pump users versus those who do not use technology
3. Pathway forward
1. Components of exploration, verification, and validation needed to develop an artificial pancreas:
1. Laboratory study, preclinical study, in-silico study, early feasibility clinical study, late feasibility clinical study, pivotal clinical study, post-approval study
4. Evidence Building: Suspend Threshold and Predicted Suspend
1. Sensor glucose value aimed to use a predictive suspend rather than a suspended threshold (programmed insulin delivery regardless of glucose levels)
1. Required involvement of engineers, regulatory, quality, manufacturing, marketing, clinical trial leaders and staff, statisticians, project managers, physician researchers, clinical trial sites
5. Aspire Trial: induced hypoglycemia (dangerous medical event that can induce unconsciousness, seizures, etc.) twice in a group of 100 patients
1. Time spent in hypoglycemia was litigated by automated system/algorithm
1. Hybrid Closed Loop; requires patient input (e.g. consumed carbohydrates)
1. Composed of glucose sensor, transmitter, infusion site, blood glucose meter, and insulin pump with closed-loop algorithm software
2. Early studies: overnight closed loop in the clinic, day and night closed loop CAMP feasibilities
3. Overnight period is without disturbances of food and activity with over 80% of the time in a target range of 70-180mg/dL
4. Challenge Testing (Intense studies done in clinics with able staff): exercise, unannounced meals, sensor false calibration, lost transmission, maximal insulin delivery
1. Success led to studies in diabetes camps, one of the most comprehensive studies done (with IRB)
5. Minimed 670G System with Smartguard Technology
1. Single-arm, non-randomized studies (with inclusion criteria)
2. Study patient flow: baseline environment, run-in phase, hotel study, in-home study, HbA1C and hypoglycemia rates
3. Observed change in A1C distribution and reduced glycemic variability from run-in to study end
6. FDA approved the first artificial pancreas, leading to the commercialization of the devices
1. 14,350 patients on Minimed 670G System
2. Nearly half a million people using the device today
7. Commercial Launch: mirrored what was seen in the pivotal trial
8. Next Step in Hybrid Closed Loop: Automated therapy is the future of diabetes management
1. One algorithm fits everyone in the population; personalization is the future of medicine, push to enhance the therapy to become more individualized and self-correct itself for meal prediction, exercise recognition, etc.
2. Requires dissection of data from thousands of individuals currently using the device 
9. Future Issues with Closed Loop
1. Still requires a group effort (big data people, researchers inside industry and at clinical research sites in academic centers, Regulatory/Quality, engineers for further product development, software/hardware, materials experts, cloud computing, marketing, sales, etc.)
2. Data is generated by users every 5 minutes; immense amounts of data that require in-depth analysis
1. Pathway to study specific user groups such as elite athletes, ill patients, etc.
10. Five Main Stages of the Evolution of Closed Loop Systems: 1) Threshold Suspend, 2) Predictive Suspend, 3) Hybrid Closed Loop, 4) Advanced Hybrid Closed Loop, 5) Towards Personalized Closed Loop
1. Each step reduced burden on the user
11. Relevance: 153,000 diabetes patients in Kazakhstan; Medtronic partnered with the nation’s government to move all children with Type 1 Diabetes onto insulin pumps
1. Goal: 50% of children on insulin pumps within two years
12. Other organizations that are helping in the fight to treat diabetes:
1. Insulin for Life brings supplies to children and during disasters
2. Life for a Child is an international program that is helping over 12,000 children and youth with diabetes in 43 countries
1. In Ethiopia, teaching standards of care to healthcare providers and endocrinologists
13. Final Thoughts
1. These medical developments are a huge, concerted group effort - it requires us to address the unmet needs and ultimately reach the pivotal trials that cannot succeed without a huge and diverse group of professionals.

Accompanying text created by Omer Baker, BS Human Biology Candidate | omerbake@usc.edu | Edited by Annie Ly, MS Regulatory Science Candidate | lyannie@usc.edu