8/7/2017 ABOUT JDRF VISION MISSION. No conflicts of interest

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1 8/7/07 No conflicts of interest DIABETES OUTCOMES BEYOND AC: TIME IN RANGE AND BEYOND Aaron Kowalski, Ph.D., JDRF Chief Mission OUR PURPOSE JDRF was Founded by Families Driven to Cure TD ABOUT JDRF Lee Ducat, Lester Salans, M.D. (NIH), Carol Lurie OUR PURPOSE JDRF s Mission and Vision THE PLAN Accelerating Progress Across the Pipeline VISION A world without type diabetes Better Outcomes MISSION Accelerating lifechanging breakthroughs to cure, prevent and treat type diabetes and its complications Accelerating Progress 6

2 8/7/07 THE PLAN Accelerating Progress Across the Pipeline Better Outcomes TO DELIVER LIFE CHANGING BREAKTHROUGHS AN ARGUMENT TO MOVE BEYOND AC CURE Restoring Insulin Independence PREVENT Preventing Symptomatic TD TREAT Improving Glucose Control Accelerating Progress 7 8 Some Rhetorical Audience Questions: WHAT IS THE MEANING OF (DIABETES) LIFE? What is the goal of diabetes treatment? CDE s in the audience? PWD in the audience? What is/are YOUR goal(s)? What is success? Is success only defined by lowering Ac? 9 0 My goals, simply put, are to be healthy and happy to return to the state that existed before TD however, there are tradeoffs Some More Rhetorical Audience Questions: How many audience members use diabetes technologies pump or CGM all of the time? How many audience members without diabetes wear a pump or CGM all of the time? Diabetes Health Work/Effort/Burden Diabetes Happiness (QoL) How many audience members without diabetes test their finger poke 6 or more times a day? ROI

3 8/7/07 Prototype AP System: ROI? Biostator: ROI? Blue Brick: ROI? Islet Transplantation: ROI? Reproduced from PLoS Medicine, e8 (00 6 CGM: ROI? CGM: ROI? Arek h hours ago Why CGM is no so good? Patient perspective #ATTD06 #diabetes #Abbott 7

4 8/7/07 How do we define better Diabetes Health and better Diabetes Happiness? What is the ROI tipping point? Diabetes Health Short Term: Ac Hypoglycemia Time in Range(s) very low, low, target, high, very high Diabetic Ketoacidosis (DKA) Severe Hypoglycemia (Seizure/coma/death) Diabetes related depression/anxiety Diabetes related eating disorders Diabetes related family issues Weight Long term: Diabetes complications Microvascular: Retinopathy, Nephropathy, Neuropathy, Gastroparesis, etc.. Macrovascular: CVD, MI, Stroke 9 0 Diabetes Happiness vs. Work/Effort/Burden Fingersticks Injections Pump set changes Wearing pump CGM site changes Wearing CGM Time interacting with diabetes Sleep interruptions Fear of hypoglycemia Fear of long term complications Cost/co pay/lack of insurance coverage ABOUT THE AC HbAc Focus on HbAc: Improved Glucose Control Reduces Risk of TD Complications (DCCT/EDIC) A measure of glycated hemoglobin Formed by irreversible nonenzymatic glycation month picture of glycemic exposure (RBC lifespan) Racial differences Genetic variants (e.g. HbS trait, HbC trait), elevated fetal hemoglobin (HbF) and chemically modified derivatives of hemoglobin (e.g. carbamylated Hb in patients with renal failure)* Anemia, increased red cell turnover, and transfusion requirements, that adversely impact HbAc as a marker of long term glycemic control Does not capture hypoglycemia Eye Disease 76% Kidney Disease 0% Nerve Disease 60% Cardio vascular 7% *NGSP.org Diabetes Control and Complications Trial (DCCT) and follow up Epidemiology of Diabetes Interventions and Complications (EDIC) trial

5 8/7/07 Mean HbAc (%) Most people do not achieve their Ac goal 00% Ac Goal = <7.% Ac Goal = <7.0% 80% 60% 0% % 9% 0% % % 7% % 0% <6 6-< -<8 8-<6 6-<0 0 Age (years) Severe hypoglycemia is still common and risk increases over time 0% 0% 0% 0% % % % 7% 9% % % 6% <6 6-< -<8 8-<6 6-< -<0 0-<6 6 Age (years) * or more events in months 6 Hyperglycemia Exposure JDRF CGM Trial The power of predictive hypo minimizer Glucose Threshold Average Hours Each Day Above Threshold Average Hours Each Day Above Threshold Average Hours Each Day Above Threshold 8- year olds - year olds + year olds 80 mg/dl. -> > > mg/dl.7 ->.9. ->.. ->.6 Buckingham et al. 0 In both data bases an individual with a mean glucose of 8 mg/dl we could predict to have an Ac of: 7% 8% or 9% or Beck R, Bergenstal R et al. Fallacy of Average D. Care Aug. 07 Perspectives in Care

6 8/7/07 What is/are the right glycemic outcome(s) Why Ac? Only validated surrogate marker for the development of longterm diabetes complications (DCCT, UKPDS, etc ) Biochemical marker of diabetes related glycation linked to pathways driving long term complications Why Not Ac? Long term measurement not reflective of day to day Not very actionable! Not reflective of hypoglycemia! Not reflective of variability Not informative regarding glucose perturbations cause and effects BEYOND THE AC ADDITIONAL DIABETES OUTCOMES ARE VALUABLE AND BETTER! ANECDOTAL REAL WORLD EXAMPLE OF IMPORTANCE OF OTHER OUTCOMES Meet the Bigfoot Family and Their Homemade Closed Loop System family their diabetes andhomemade closed loop system# 0,000 hours of at home AP Defining value beyond Ac: burden/qol metrics the nighttime security it has given me has been even more amazing I have the incredible and previously unimaginable joy of waking up with a blood sugar at or around 00 nearly every single day. No waking up with extreme thirst and irritability; no waking up groggy with a low headache. When Bryan travels, I no longer run myself on the higher side of my range overnight for fear of having a nighttime low alone. A great deal of the burden of TD was taken off my shoulders, Having Sam on the system was absolutely amazing and life changing I felt confident going to sleep His most recent AC, post honeymoon, was.8% with % hypoglycemia. What is most amazing about that AC is how little we worked for it. We did not lose sleep over it; we did not stress over it. The system not only kept Sam s blood sugars in range, but it kept us all feeling SAFE. 6

7 8/7/07 Additional Critical Outcomes Time in Range(s) Hypoglycemia Hyperglycemia DKA Patient Reported Outcomes (PRO s) Why Time in Range(s)? Provides both hyper and hypoglycemia transparency Provides direct visibility to both short term and long term diabetes risks Provides a more physiologic target for improved glucose control Provides the best representation of diabetes glycemic health Why Not? What is the ideal range? 70 0mg/dL (.9.8mM)? 70 80mg/dL 9.9 0mM)? What is the goal? How much time in each range? CGM dependent (to a large degree) 7 8 TD OUTCOMES PROGRAM Additional outcomes necessary to fully assess diabetes outcomes and therapies Current State Focus on hemoglobin Ac (HbAc) as a population based predictor of complications TD Community Desired State Expanded set of diabetes outcomes that reach beyond Ac to better reflect glucose control and how patients feel, function and survive POLICY & ADVOCACY JDRF worked with many stakeholders and FDA to develop AP system development guidance Provides pathway to commercial systems Primary outcome may be Ac, but also may be Time in Range, Hypo, etc We are currently working on similar pathway for drugs and biologics 9 0 FDA Workshop Important Milestone TD Outcomes Program Dr. Aaron Kowalski July, 07 7

8 8/7/07 TD OUTCOMES PROGRAM OVERVIEW TD clinician expertise Steering Committee Lawrence Blonde, MD Sripriya Raman, MD Kent Reifschneider, MD Karen Rubin, MD Stuart Weinzimer, MD TD OUTCOMES PROGRAM OVERVIEW Clinician experts are focused on five outcomes based on prioritization poll Prioritized outcomes Molly McElwee Malloy, RN, CDE Karen Harriman, FNP BC, MSN, CDE Paul Madden, MEd Alicia McAuliffe Fogarty, PhD Gina Agiostratidou, PhD, MBA Steve Griffen, MD Aaron Kowalski, PhD Weighted Rank Scores Anne Peters, MD Evgenia Gourgari, MD Henry Anhalt, DO Dana Ball Kenneth Scheer 0 Total Daily Insulin Weight or BMI Insulin (TDI) Resistance (IR) (Wt/BMI) DKA Patient Hyperglycemia Reported (Hyper) HbAc Time in Range Hypoglycemia (TIR) (Hypo) Outcomes (PROs) TD OUTCOMES PROGRAM OVERVIEW Multi step process to achieve consensus for each outcome Review existing evidence Over 00 articles reviewed Develop draft definitions Based on evidence review Multiple options presented Seek TD community input Advisory Committees review and respond to clinical evidence and draft definitions Consensus definition Steering Committee meets to discuss clinical evidence and Advisory Committee input to reach consensus Draft consensus reviewed by SC Public Commenting closed March, 07 Final Consensus Summer 07 CONSENSUS DEFINITIONS 6 Hypoglycemia Hyperlycemia Level Glycemic Criteria/Description Level Glycemic Criteria/Description Level Level mg/dl (.0 mmol/l) Glucose < 70 mg/dl (.9 mmol/l) Glucose < mg/dl (<.0 mmol/l) Level Elevated Glucose 80 mg/dl (0 mmol/l )< Glucose < 0 mg/dl (.9 mmol/l) Level A severe event characterized by altered mental and/or physical status requiring assistance Level Very Elevated Glucose Glucose > 0 mg/dl (.9 mmol/l) 7 8 8

9 8/7/07 Time in Range DKA Glycemic Criteria/Description Glycemic Criteria/Description Percentage of readings in the range of 70 mg/dl 80 mg/dl ( mmol/l) per unit of time Elevated serum or urine ketones (greater than the upper limit of the normal range) Serum bicarbonate < mmol/l or Blood ph < PROs A variety of validated tools and measures (including surveys and questionnaires) of some PROs for youth and adults with TD are available and are used in clinical studies, including those for diabetes distress and fear of hypoglycemia, however, there are limitations Ongoing work in this area to continue and additional work to be undertaken so that as more advanced and specific tools are developed PATIENT PREFERENCE STUDY UNDERWAY Existing evidence did not support recommendations for specific PRO measures to be used in clinical trials TD Outcomes Program Summary Core CGM Metrics Use of All Clinically Meaningful Outcomes HbAc Hypoglycemia Hyperglycemia Time in Range PROs Risk Hypo/Hyper: LBGI HBGI *Bergenstal 9

10 8/7/07 Beyond Ac: A Critical Conversation CGM Data, It is Time To: Standardize Visualize Utilize in Research & Practice *Dr. Rich Bergenstal *Bergenstal Easier Access to Data Free, open source, multi device USE OF ADDITIONAL OUTCOMES IS CRITICAL ACROSS STAKEHOLDERS 60 0

11 8/7/07 THE PLAN Accelerating Progress Across the Pipeline Importance to different stakeholders Better Outcomes FDA and global regulators: Guidance documents Approval of novel therapies Payers Payment for additional outcomes CMS coverage of CGM Clinicians Guidance of therapy options PWD More therapy options suited to their needs Better outcomes!! Accelerating Progress 6 6 Summary Diabetes No Limits! The Ac metric, while very valuable, does not meet the needs of current diabetes treatment strategies Time in Range is a better measure of glycemic control in PWD Other metrics are also very valuable both glycemic and importantly QoL/Burden We must develop future tools that improve diabetes health and happiness concomitantly Outcomes beyond Ac need to be valued by all stakeholders JDRF is partnering with the Helmsley Charitable Trust, the TDx and many other stakeholders to improve the valuation of outcomes beyond Ac with regulators and payers 6 Acknowledgments: JDRF Team Thank You! Questions 66