NANS I3

Steve Adler

December 6, 2012

Indications for Use

• U.S.– Infumorph

• Europe– Morphine and Baclofen

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

Examples of Poor Accuracy

Introduction

• Product development process for accurate pump– Requirements– Solutions – valve gated technology– Bench or verification tests

• Clinical study results• Clinical significance, next steps

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

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

• Dose Accuracy 98%• No temp, pressure,

reservoir volumeeffects

• Longevity >10 years• Designed to deliver

any compound• Can deliver micro-

doses

Prometra Pump

Dose RegulationValve-Gated Dosing Chamber

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.

Bench Testing Results

High ex

it pressu

re (16.7psia

)

Low ex

it pressu

re (10.1psia

)

High Te

mperature

(40°C)

Low Te

mperature (3

5°C)

Variety

of Enviro

nmental

Exposu

res - m

inimum ac

curac

y

Variety

of Enviro

nmental

Exposu

res - m

aximum ac

curac

y

-15%-10%

-5%0%5%

10%15%

Testing Condition

Aver

age

Pum

p Pu

lse

Volu

me

Perc

ent D

iffer

ence

Ongoing Life Testing

Pump B0

20

40

60

80

100

120

Aver

age

Accu

racy

(%)

after

7+

year

s

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 = 2,073Number of Patients = 148

Mean 98.4Standard Error 0.5

90% Confidence Interval (97.6 – 99.2)

Accuracy by Flow Rate

•Flow rate range: 0-1.5 mL/day•No statistically significant differences between flow rate categories

(0.0, 0.14] (319) (0.14, 0.24] (347) (0.24, 0.32] (368) (0.32, 0.45] (659) ≥0.45 (380)0

20

40

60

80

100

120

Flow Rate in mL/day (total visits)

Mea

n Ac

cura

cy (%

)

Accuracy by Months Post-Implantation

•No statistically significant differences between any of the time-points

3 (132) 6 (123) 9 (106) 12 (93) 15 (82) 18 (70) 21 (68) 24 (66) 27 (67) 30 (65) 33 (62) 36 (46) 39 (21) 42 (5)0

20

40

60

80

100

120

Months Post-Implantation (total visits)

Mea

n Ac

cura

cy (%

)

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].

[0.0, 4.0] (488) (4.0, 8.0] (925) (8.0, 12.0] (333) (12.0, 16.0] (246) (16.0, 20.0] (81)0

20

40

60

80

100

120

Residual Volume in mL (total visits)

Mea

n Ac

cura

cy (%

)

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

(0.0, 10.0] (636) (10.0, 25.0] (520) (25.0, 50.0] (380) 50 (537)0

20

40

60

80

100

120

Concentration in mg/mL (total visits)

Mea

n Ac

cura

cy (%

)

Ongoing Continued EvaluationLSU Health Science Center

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.

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

Clinical Significance?

• Scheduling of refill visits• Possibly avoiding overdose/underdose, withdrawal

symptoms• Drug dependent• Micro-dosing• Future applications

Intraparenchymal (IPa)

Intracranial Drug AdministrationICV

IT

Intracerebroventricular (ICV)

Clinical Need for Accuracy in Drug Delivery to the Brain

• limit exposure to other organs• deliver complex dosing pattern• greatly reduce effective drug dosage

Conclusions

• Achieved design goals– 98% accurate, independent of external factors

• Confirmed in bench tests• Validated in clinical trials• Clinical significance depends on disease/drugs