Transforming Evidence Generation for Drug Label Changes: A Case Study.

Computer Modeling and Simulation (CM&S) provides the opportunity to drastically reduce clinical trial patient burden and advance regulatory decision making. At the suggestion of the US Food and Drug Administration (FDA), MannKind Corporation and Nudge BG submitted an application to the FDA Model-Informed Drug Development (MIDD) pilot program to support a label change for the initial dose of Afrezza® (insulin human), a novel inhalable insulin with a rapid pharmacokinetic and pharmacodynamic profile. The MIDD pilot program demonstrates the FDA's commitment to advancing regulatory science through the adoption of evidence generated by CM&S. A simulation framework was developed based on empirical data. It was used to generate evidence to support the label change. Briefing packages and presentations were prepared for two meetings with the FDA, over a period of four months. The model was thoroughly characterized, determined to be low risk for the question of interest, and submitted along with additional clinical evidence for validation. The FDA found the simulation framework to be helpful in providing insights into the question of interest and provides reasonable glycemic outcome predictions. At the conclusion of the MIDD paired meetings, FDA personnel from the Center for Drug Evaluation and Research review team accepted the simulation and requested additional, traditional clinical evidence to support the proposed label change. In the post-meeting comments, the FDA invited MannKind to submit a proposal for a data package including the CM&S evidence in a Type C meeting for further discussion on the label change. This MIDD pilot experience suggests that CM&S is a credible method for evidence generation. Collaboration between sponsor organizations as well as all stakeholders in the FDA, including proponents of CM&S, can further support regulatory decision-making. The learnings from early participants will allow the program to reach its full potential and thereby ultimately benefit patients, sponsors, and FDA.

Reduction in Postprandial Peak Glucose With Increased Technosphere Insulin Dosage.

BACKGROUND: Technosphere Insulin (TI) is an ultra-rapid-acting inhaled insulin. This study assessed the mean peak two-hour postprandial glucose concentration with the initial TI dose (dose 1) calculated per the current label (United State Prescribing Information) compared with a ~2× higher dose (dose 2). Secondary objectives were to evaluate hypoglycemia within the two-hour postprandial period, evaluate change in forced expiratory volume in one second (FEV1) before and after the two-hour postprandial period, and monitor for other adverse events. METHODS: Twenty patients with diabetes, on basal-bolus insulin therapy, received an initial dose 1 of TI followed by the higher dose 2, one to three days later. Subjects received an identical meal for both visits, and TI doses were administered immediately prior to the meal. RESULTS: The higher dose 2 provided significant reductions in mean postprandial glucose excursion (PPGE) in the two-hour postprandial period starting from 45 minutes (P = .008) to 120 minutes (P < .0001). Mean peak glucose was reduced from 228.6 to 179.3 mg/dL (P < .001) at two hours. Two hypoglycemic events (one level 1, one level 2) were observed in a single subject during the two-hour postprandial period with dose 2. There were no significant changes in FEV1 after either dose of TI. CONCLUSIONS: The higher dose 2 reduced PPGE versus the current label recommended dose 1 within the two-hour postprandial timeframe without any new safety concerns. When confirmed with a larger study, this higher TI dosing recommendation may help patients and clinicians minimize immediate postprandial hyperglycemia when titrating TI for prandial glucose control.

Changes in phytochemical composition, bioactivity and in vitro digestibility of guayusa leaves (Ilex guayusa Loes.) in different ripening stages.

BACKGROUND: Guayusa (Ilex guayusa Loes.) leaves, native of the Ecuadorian Amazon, are popularly used for preparing teas. This study aimed to assess the influence of leaf age on the phenolic compounds and carotenoids and the bioactivity and digestibility (in vitro) of aqueous and hydroalcoholic leaf extracts. RESULTS: In total, 14 phenolic compounds were identified and quantified. Chlorogenic acid and quercetin-3-O-hexose were the main representatives of the hydroxycinnamic acids and flavonols respectively. Seven carotenoids were quantified, lutein being the main compound. Ripening affected phenolic content significantly, but there was no significant difference in carotenoid content. Antioxidant capacity, measured by the DPPH• method, was also significantly affected by leaf age. The measurement of in vitro digestibility showed a decrease in phenolic content (59%) as well as antioxidant capacity, measured by the ABTS•+ method, in comparison with initial conditions of the guayusa infusion. Antibacterial and anti-inflammatory activities were assayed with young leaves owing to their higher phenolic contents. Guayusa did not show any antibacterial activity against Escherichia coli ATCC 25922 or Staphylococcus aureus ATCC 25923. Finally, the hydroalcoholic and aqueous extracts exhibited high in vitro anti-inflammatory activity (>65%). CONCLUSION: Young guayusa leaves have potential applications as a functional ingredient in food and pharmaceutical industries. © 2017 Society of Chemical Industry.

Moving Toward a Unified Platform for Insulin Delivery and Sensing of Inputs Relevant to an Artificial Pancreas.

Advances in insulin pump and continuous glucose monitoring technology have primarily focused on optimizing glycemic control for people with type 1 diabetes. There remains a need to identify ways to minimize the physical burden of this technology. A unified platform with closely positioned or colocalized interstitial fluid glucose sensing and hormone delivery components is a potential solution. Present challenges to combining these components are interference of glucose sensing from proximate insulin delivery and the large discrepancy between the life span of current insulin infusion sets and glucose sensors. Addressing these concerns is of importance given that the future physical burden of this technology is likely to be even greater with the ongoing development of the artificial pancreas, potentially incorporating multiple hormone delivery, glucose sensing redundancy, and sensing of other clinically relevant nonglucose biochemical inputs.

Redundancy in Glucose Sensing: Enhanced Accuracy and Reliability of an Electrochemical Redundant Sensor for Continuous Glucose Monitoring.

BACKGROUND: Current electrochemical glucose sensors use a single electrode. Multiple electrodes (redundancy) may enhance sensor performance. We evaluated an electrochemical redundant sensor (ERS) incorporating two working electrodes (WE1 and WE2) onto a single subcutaneous insertion platform with a processing algorithm providing a single real-time continuous glucose measure. METHODS: Twenty-three adults with type 1 diabetes each wore two ERSs concurrently for 168 hours. Post-insertion a frequent sampling test (FST) was performed with ERS benchmarked against a glucose meter (Bayer Contour Link). Day 4 and 7 FSTs were performed with a standard meal and venous blood collected for reference glucose measurements (YSI and meter). Between visits, ERS was worn with capillary blood glucose testing ≥8 times/day. Sensor glucose data were processed prospectively. RESULTS: Mean absolute relative deviation (MARD) for ERS day 1-7 (3,297 paired points with glucose meter) was (mean [SD]) 10.1 [11.5]% versus 11.4 [11.9]% for WE1 and 12.0 [11.9]% for WE2; P < .0001. ERS Clarke A and A+B were 90.2% and 99.8%, respectively. ERS day 4 plus day 7 MARD (1,237 pairs with YSI) was 9.4 [9.5]% versus 9.6 [9.7]% for WE1 and 9.9 [9.7]% for WE2; P = ns. ERS day 1-7 precision absolute relative deviation (PARD) was 9.9 [3.6]% versus 11.5 [6.2]% for WE1 and 10.1 [4.4]% for WE2; P = ns. ERS sensor display time was 97.8 [6.0]% versus 91.0 [22.3]% for WE1 and 94.1 [14.3]% for WE2; P < .05. CONCLUSIONS: Electrochemical redundancy enhances glucose sensor accuracy and display time compared with each individual sensing element alone. ERS performance compares favorably with 'best-in-class' of non-redundant sensors.