1. NANS I 3 Steve Adler December 6, 2012

2. Indications for Use U.S. –Infumorph Europe –Morphine and Baclofen

3. Accuracy Definition: Accuracy refers to the correctness of a single measurement. Accuracy is determined by comparing the measurement against the true or accepted value. For our purposes, the true or accepted value is the programmed dose

4. Examples of Poor Accuracy

5. Introduction Product development process for accurate pump –Requirements –Solutions – valve gated technology –Bench or verification tests Clinical study results Clinical significance, next steps

6. Design Considerations for Accurate (Precise, Durable) Pump Prior pumps had shortcomings Important design considerations –Accuracy of drug delivery –Accuracy of reported volume in reservoir –Consistency of amount received by the patient over time –Limit any variation in flow rate due to programmed dose, battery age, reservoir volume, temperature or pressure –Ability to accurately deliver micro-doses –No variation in device performance over a wide range of concentrations and compounds

7. Product Development New technology was required to design a pump with a an accurate dosing mechanism –The challenges were to design A completely different flow regulating mechanism Electronics that would allow precise timing and provide redundant safety checks A power supply with exceptional longevity Communication capabilities that were insusceptible to interference and able to prevent programming errors

8. Dose Accuracy 98% No temp, pressure, reservoir volume effects Longevity >10 years Designed to deliver any compound Can deliver micro- doses Prometra Pump

9. Dose Regulation Valve-Gated Dosing Chamber

10. Bench Testing Extensive bench testing was performed to confirm overall accuracy, as well as accuracy under a variety of conditions. –Pressure extremes –Temperature extremes –Various programmable rates –Various reservoir fill levels –Various environmental exposures Temperature cycling Electric shock exposure Vibration testing Multiple sterilization cycles –Drug flow accuracy was within specification in each testing scenario.

11. Bench Testing Results

12. Ongoing Life Testing

13. PUMP Clinical Study: Accuracy Results Accuracy was calculated as the delivered (volumetrically determined) to programmed (DP) drug volume ratio –Numerator: sum of delivered drug volumes over all (scheduled and unscheduled) valid fill/refill sessions per patient –Denominator: sum of programmed drug volumes over all (scheduled and unscheduled) valid fill/refill sessions per patient Overall accuracy is calculated by averaging the per patient DP ratios Accuracy Results (%) Number of Refills = 2,073 Number of Patients = 148 Mean98.4 Standard Error0.5 90% Confidence Interval(97.6 – 99.2)

14. Accuracy by Flow Rate Flow rate range: 0-1.5 mL/day No statistically significant differences between flow rate categories

15. Accuracy by Months Post-Implantation No statistically significant differences between any of the time-points

16. Accuracy by Residual Volume (12.0-16.0] was lower than [0.0-4.0] (p=0.0119) (16.0-20.0] was lower than all other categories (p<0.0001) Mean accuracy was 100% in the lowest residual volume category (0.0, 4.0].

17. Accuracy by Concentration Morphine concentration range: 1-50 mg/mL No significant differences between concentration categories No pump failures or other complications occurred related to drug concentration

18. Ongoing Continued Evaluation LSU Health Science Center

19. Durability and Longevity The only moving parts are the valves Fewer moving parts and a simpler design mean less opportunity for complications The valves require very little energy Promotes longer battery life, requiring fewer replacement surgeries over the course of a patient’s IT therapy.

20. Accuracy With Other Drugs? Proper function of pumps can be affected by the drug being delivered. –Concentration, molecular size, and corrosion of pump materials can have serious effects Clinical trial results indicate that the Prometra Pump is very accurate when delivering morphine sulfate –Experience with both Infumorph ® and compounded morphine at a wide range of concentrations What about other drugs? –Accuracy should be unaffected by the type of drug in the pump. 1 –The titanium dosing chamber of the Prometra Pump simply measures the exact volume of the fluid to be delivered. This measurement is unaffected by type of fluid in the chamber 1 Yearwood, T. Results of Secondary Pain Medications to Improve Pain Outcomes in The Prometra Programmable Infusion Pump. Poster Presentation at the 11th Annual ASRA Pain Medicine Meeting, November 2012

21. Clinical Significance? Scheduling of refill visits Possibly avoiding overdose/underdose, withdrawal symptoms Drug dependent Micro-dosing Future applications

22. Intraparenchymal (IPa) Intracranial Drug Administration ICV IT Intracerebroventricular (ICV)

23. Clinical Need for Accuracy in Drug Delivery to the Brain limit exposure to other organs deliver complex dosing pattern greatly reduce effective drug dosage

24. Conclusions Achieved design goals –98% accurate, independent of external factors Confirmed in bench tests Validated in clinical trials Clinical significance depends on disease/drugs